470 results on '"Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics"'
Search Results
2. The e13a3 (b2a3) and e14a3 (b3a3) BCR::ABL1 isoforms are resistant to asciminib.
- Author
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Leske IB and Hantschel O
- Subjects
- Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-abl genetics, Proto-Oncogene Proteins c-abl metabolism, Niacinamide analogs & derivatives, Pyrazoles, Fusion Proteins, bcr-abl genetics, Drug Resistance, Neoplasm genetics, Protein Isoforms genetics
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- 2024
- Full Text
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3. Absence of ABL1 exon 2-encoded SH3 residues in BCR::ABL1 destabilizes the autoinhibited kinase conformation and confers resistance to asciminib.
- Author
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Leyte-Vidal A, DeFilippis R, Outhwaite IR, Kwan I, Lee JY, Leavitt C, Miller KB, Rea D, Rangwala AM, Lou K, Patel S, Alvarez A, Shokat KM, Bahar I, Seeliger MA, and Shah NP
- Subjects
- Humans, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, src Homology Domains, Proto-Oncogene Proteins c-abl genetics, Protein Conformation, Pyrazoles pharmacology, Pyrazoles therapeutic use, Niacinamide analogs & derivatives, Fusion Proteins, bcr-abl genetics, Drug Resistance, Neoplasm genetics, Exons genetics
- Published
- 2024
- Full Text
- View/download PDF
4. Point-of-care BCR::ABL1 transcript monitoring using capillary dried blood in chronic myeloid leukemia patients.
- Author
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Sala-Torra O, Beppu L, Wu Q, Welch E, Berthier E, Radich JP, and Oehler VG
- Subjects
- Humans, Point-of-Care Systems, Male, Female, Dried Blood Spot Testing methods, Middle Aged, Aged, Adult, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Fusion Proteins, bcr-abl genetics
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- 2024
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5. Repurposing pexmetinib as an inhibitor of TKI-resistant BCR::ABL1.
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Fontana D, Malighetti F, Villa M, Zambon A, Gambacorti-Passerini C, and Mologni L
- Subjects
- Humans, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors pharmacology, Fusion Proteins, bcr-abl genetics, Fusion Proteins, bcr-abl antagonists & inhibitors, Drug Resistance, Neoplasm genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Drug Repositioning methods
- Published
- 2024
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6. TIF1β activates leukemic transcriptional program in HSCs and promotes BCR::ABL1-induced myeloid leukemia.
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Morii M, Kubota S, Iimori M, Yokomizo-Nakano T, Hamashima A, Bai J, Nishimura A, Tasaki M, Ando Y, Araki K, and Sashida G
- Subjects
- Animals, Mice, Humans, Gene Expression Regulation, Leukemic, Tripartite Motif-Containing Protein 28 metabolism, Tripartite Motif-Containing Protein 28 genetics, Transcription, Genetic, Fusion Proteins, bcr-abl genetics, Fusion Proteins, bcr-abl metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism
- Abstract
TIF1β/KAP1/TRIM28, a chromatin modulator, both represses and activates the transcription of genes in normal and malignant cells. Analyses of datasets on leukemia patients revealed that the expression level of TIF1β was increased in patients with chronic myeloid leukemia at the blast crisis and acute myeloid leukemia. We generated a BCR::ABL1 conditional knock-in (KI) mouse model, which developed aggressive myeloid leukemia, and demonstrated that the deletion of the Tif1β gene inhibited the progression of myeloid leukemia and showed longer survival than that in BCR::ABL1 KI mice, suggesting that Tif1β drove the progression of BCR::ABL1-induced leukemia. In addition, the deletion of Tif1β sensitized BCR::ABL1 KI leukemic cells to dasatinib. The deletion of Tif1β decreased the expression levels of TIF1β-target genes and chromatin accessibility peaks enriched with the Fosl1-binding motif in BCR::ABL1 KI stem cells. TIF1β directly bound to the promoters of proliferation genes, such as FOSL1, in human BCR::ABL1 cells, in which TIF1β and FOSL1 bound to adjacent regions of chromatin. Since the expression of Fosl1 was critical for the enhanced growth of BCR::ABL1 KI cells, Tif1β and Fosl1 interacted to activate the leukemic transcriptional program in and cellular function of BCR::ABL1 KI stem cells and drove the progression of myeloid leukemia., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
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7. Combination therapies with ponatinib and asciminib in a preclinical model of chronic myeloid leukemia blast crisis with compound mutations.
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Curik N, Laznicka A, Polivkova V, Krizkova J, Pokorna E, Semerak P, Suchankova P, Burda P, Hochhaus A, and Machova Polakova K
- Subjects
- Humans, Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Mice, Fusion Proteins, bcr-abl genetics, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors pharmacology, Niacinamide analogs & derivatives, Pyrazoles, Pyridazines therapeutic use, Pyridazines administration & dosage, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Imidazoles therapeutic use, Imidazoles administration & dosage, Mutation, Blast Crisis genetics, Blast Crisis drug therapy, Blast Crisis pathology
- Published
- 2024
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- View/download PDF
8. Are there new relevant therapeutic endpoints in the modern era of the BCR::ABL1 tyrosine kinase inhibitors in chronic myeloid leukemia?
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Kantarjian H, Branford S, Breccia M, Cortes J, Haddad FG, Hochhaus A, Hughes T, Issa GC, Jabbour E, Nicolini FE, Sasaki K, and Xavier-Mahon F
- Subjects
- Humans, Proto-Oncogene Proteins c-abl genetics, Proto-Oncogene Proteins c-abl antagonists & inhibitors, Fusion Proteins, bcr-abl antagonists & inhibitors, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Tyrosine Kinase Inhibitors therapeutic use
- Published
- 2024
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9. State-transition modeling of blood transcriptome predicts disease evolution and treatment response in chronic myeloid leukemia.
- Author
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Frankhouser DE, Rockne RC, Uechi L, Zhao D, Branciamore S, O'Meally D, Irizarry J, Ghoda L, Ali H, Trent JM, Forman S, Fu YH, Kuo YH, Zhang B, and Marcucci G
- Subjects
- Mice, Animals, Fusion Proteins, bcr-abl metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Tetracyclines therapeutic use, Drug Resistance, Neoplasm, Transcriptome, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Abstract
Chronic myeloid leukemia (CML) is initiated and maintained by BCR::ABL which is clinically targeted using tyrosine kinase inhibitors (TKIs). TKIs can induce long-term remission but are also not curative. Thus, CML is an ideal system to test our hypothesis that transcriptome-based state-transition models accurately predict cancer evolution and treatment response. We collected time-sequential blood samples from tetracycline-off (Tet-Off) BCR::ABL-inducible transgenic mice and wild-type controls. From the transcriptome, we constructed a CML state-space and a three-well leukemogenic potential landscape. The potential's stable critical points defined observable disease states. Early states were characterized by anti-CML genes opposing leukemia; late states were characterized by pro-CML genes. Genes with expression patterns shaped similarly to the potential landscape were identified as drivers of disease transition. Re-introduction of tetracycline to silence the BCR::ABL gene returned diseased mice transcriptomes to a near healthy state, without reaching it, suggesting parts of the transition are irreversible. TKI only reverted the transcriptome to an intermediate disease state, without approaching a state of health; disease relapse occurred soon after treatment. Using only the earliest time-point as initial conditions, our state-transition models accurately predicted both disease progression and treatment response, supporting this as a potentially valuable approach to time clinical intervention, before phenotypic changes become detectable., (© 2024. The Author(s).)
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- 2024
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10. Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials.
- Author
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Jabbour E, Apperley J, Cortes J, Rea D, Deininger M, Abruzzese E, Chuah C, DeAngelo DJ, Hochhaus A, Lipton JH, Mauro M, Nicolini F, Pinilla-Ibarz J, Rosti G, Rousselot P, Shah NP, Talpaz M, Vorog A, Ren X, and Kantarjian H
- Subjects
- Humans, Drug Resistance, Neoplasm, Imidazoles therapeutic use, Imidazoles pharmacology, Fusion Proteins, bcr-abl genetics, Protein Kinase Inhibitors pharmacology, Leukemia, Myeloid, Chronic-Phase drug therapy, Leukemia, Myeloid, Chronic-Phase genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Pyridazines therapeutic use, Pyridazines pharmacology, Antineoplastic Agents therapeutic use, Antineoplastic Agents pharmacology
- Abstract
Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust and durable responses at 45 mg/day in patients with CP-CML resistant to second-generation TKIs in the PACE trial. However, cardiovascular toxicities, including arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. To assess the dose-response relationship and the effect on the safety of ponatinib, we examined the outcomes of patients with CP-CML enrolled in PACE and OPTIC who received 45 mg/day of ponatinib. A propensity score analysis was used to evaluate AOEs across both trials. Survival rates and median time to achieve ≤1% BCR::ABL1
IS in OPTIC were similar or better than in PACE. The outcomes of patients with T315I mutations were robust in both trials. Patients in OPTIC had a lower exposure-adjusted incidence of AOEs compared with those in PACE. This analysis demonstrates that response-based dosing for ponatinib improves treatment tolerance and mitigates cardiovascular risk., (© 2024. The Author(s).)- Published
- 2024
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11. The SNP rs460089 in the gene promoter of the drug transporter OCTN1 has prognostic value for treatment-free remission in chronic myeloid leukemia patients treated with imatinib.
- Author
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Machova Polakova K, Albeer A, Polivkova V, Krutska M, Vlcanova K, Curik N, Fabarius A, Klamova H, Spiess B, Waller CF, Brümmendorf TH, Dengler J, Kunzmann V, Burchert A, Belohlavkova P, Mustjoki S, Faber E, Mayer J, Zackova D, Panayiotidis P, Richter J, Hjorth-Hansen H, Kamińska M, Płonka M, Szczepanek E, Szarejko M, Bober G, Hus I, Grzybowska-Izydorczyk O, Wasilewska E, Paczkowska E, Niesiobędzka-Krężel J, Giannopoulos K, Mahon FX, Sacha T, Saußele S, and Pfirrmann M
- Subjects
- Humans, Imatinib Mesylate therapeutic use, Prognosis, Protein Kinase Inhibitors therapeutic use, Membrane Transport Proteins therapeutic use, Treatment Outcome, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Antineoplastic Agents adverse effects
- Abstract
Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60-82%) compared to patients with GG (51%, 95% CI: 41-61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR., (© 2023. The Author(s).)
- Published
- 2024
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12. Identification of multivariable microRNA and clinical biomarker panels to predict imatinib response in chronic myeloid leukemia at diagnosis.
- Author
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Wu A, Yen R, Grasedieck S, Lin H, Nakamoto H, Forrest DL, Eaves CJ, and Jiang X
- Subjects
- Humans, Imatinib Mesylate therapeutic use, Imatinib Mesylate pharmacology, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors pharmacology, Biomarkers, MicroRNAs genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Abstract
Imatinib Mesylate (imatinib) was once hailed as the magic bullet for chronic myeloid leukemia (CML) and remains a front-line therapy for CML to this day alongside other tyrosine kinase inhibitors (TKIs). However, TKI treatments are rarely curative and patients are often required to receive life-long treatment or otherwise risk relapse. Thus, there is a growing interest in identifying biomarkers in patients which can predict TKI response upon diagnosis. In this study, we analyze clinical data and differentially expressed miRNAs in CD34
+ CML cells from 80 patients at diagnosis who were later classified as imatinib-responders or imatinib-nonresponders. A Cox Proportional Hazard (CoxPH) analysis identified 16 miRNAs that were associated with imatinib nonresponse and differentially expressed in these patients. We also trained a machine learning model with different combinations of the 16 miRNAs with and without clinical parameters and identified a panel with high predictive performance based on area-under-curve values of receiver-operating-characteristic and precision-recall curves. Interestingly, the multivariable panel consisting of both miRNAs and clinical features performed better than either miRNA or clinical panels alone. Thus, our findings may inform future studies on predictive biomarkers and serve as a tool to develop more optimized treatment plans for CML patients in the clinic., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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13. European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia.
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Cross NCP, Ernst T, Branford S, Cayuela JM, Deininger M, Fabarius A, Kim DDH, Machova Polakova K, Radich JP, Hehlmann R, Hochhaus A, Apperley JF, and Soverini S
- Subjects
- Humans, Recurrence, Protein Kinase Inhibitors, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy
- Abstract
From the laboratory perspective, effective management of patients with chronic myeloid leukemia (CML) requires accurate diagnosis, assessment of prognostic markers, sequential assessment of levels of residual disease and investigation of possible reasons for resistance, relapse or progression. Our scientific and clinical knowledge underpinning these requirements continues to evolve, as do laboratory methods and technologies. The European LeukemiaNet convened an expert panel to critically consider the current status of genetic laboratory approaches to help diagnose and manage CML patients. Our recommendations focus on current best practice and highlight the strengths and pitfalls of commonly used laboratory tests., (© 2023. The Author(s).)
- Published
- 2023
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14. External validation of the predictive scoring systems for molecular responses in chronic myeloid leukaemia receiving initial imatinib-therapy.
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Qi F, Zhang X, Gale RP, Liu B, Huang J, Huang X, and Jiang Q
- Subjects
- Humans, Imatinib Mesylate therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Antineoplastic Agents therapeutic use, Leukemia, Myeloid
- Published
- 2023
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15. Genetic separation of chronic myeloid leukemia stem cells from normal hematopoietic stem cells at single-cell resolution.
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Chen Y, Möbius S, Riege K, Hoffmann S, Hochhaus A, Ernst T, and Rudolph KL
- Subjects
- Humans, Hematopoietic Stem Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myeloid, Leukemia, Myeloid, Acute genetics
- Published
- 2023
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16. Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results.
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Mauro MJ, Hughes TP, Kim DW, Rea D, Cortes JE, Hochhaus A, Sasaki K, Breccia M, Talpaz M, Ottmann O, Minami H, Goh YT, DeAngelo DJ, Heinrich MC, Gómez-García de Soria V, le Coutre P, Mahon FX, Janssen JJWM, Deininger M, Shanmuganathan N, Geyer MB, Cacciatore S, Polydoros F, Agrawal N, Hoch M, and Lang F
- Subjects
- Humans, Fusion Proteins, bcr-abl genetics, Mutation, Protein Kinase Inhibitors adverse effects, Drug Resistance, Neoplasm, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Neutropenia chemically induced, Antineoplastic Agents therapeutic use
- Abstract
Asciminib is approved for patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10-200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achieved BCR::ABL1 ≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population., (© 2023. The Author(s).)
- Published
- 2023
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17. Pathogenesis and management of accelerated and blast phases of chronic myeloid leukemia.
- Author
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Senapati J, Jabbour E, Kantarjian H, and Short NJ
- Subjects
- Humans, Blast Crisis drug therapy, Protein Kinase Inhibitors therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Hematopoietic Stem Cell Transplantation
- Abstract
The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) has been a model for cancer therapy development. Though most patients with CML have a normal quality and duration of life with TKI therapy, some patients progress to accelerated phase (AP) and blast phase (BP), both of which have a relatively poor prognosis. The rates of progression have reduced significantly from over >20% in the pre-TKI era to <5% now, largely due to refinements in CML therapy and response monitoring. Significant insights have been gained into the mechanisms of disease transformation including the role of additional cytogenetic abnormalities, somatic mutations, and other genomic alterations present at diagnosis or evolving on therapy. This knowledge is helping to optimize TKI therapy, improve prognostication and inform the development of novel combination regimens in these patients. While patients with de novo CML-AP have outcomes almost similar to CML in chronic phase (CP), those transformed from previously treated CML-CP should receive second- or third- generation TKIs and be strongly considered for allogeneic stem cell transplantation (allo-SCT). Similarly, patients with transformed CML-BP have particularly dismal outcomes with a median survival usually less than one year. Combination regimens with a potent TKI such as ponatinib followed by allo-SCT can achieve long-term survival in some transformed BP patients. Regimens including venetoclax in myeloid BP or inotuzumab ozogamicin or blinatumomab in lymphoid BP might lead to deeper and longer responses, facilitating potentially curative allo-SCT for patients with CML-BP once CP is achieved. Newer agents and novel combination therapies are further expanding the therapeutic arsenal in advanced phase CML., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2023
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18. Minimal residual disease in BCR::ABL1-positive acute lymphoblastic leukemia: different significance in typical ALL and in CML-like disease.
- Author
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Zuna J, Hovorkova L, Krotka J, Koehrmann A, Bardini M, Winkowska L, Fronkova E, Alten J, Koehler R, Eckert C, Brizzolara L, Trkova M, Stuchly J, Zimmermann M, De Lorenzo P, Valsecchi MG, Conter V, Stary J, Schrappe M, Biondi A, Trka J, Zaliova M, Cazzaniga G, and Cario G
- Subjects
- Child, Humans, Fusion Proteins, bcr-abl genetics, Neoplasm, Residual genetics, Retrospective Studies, Acute Disease, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Recently, we defined "CML-like" subtype of BCR::ABL1-positive acute lymphoblastic leukemia (ALL), resembling lymphoid blast crisis of chronic myeloid leukemia (CML). Here we retrospectively analyzed prognostic relevance of minimal residual disease (MRD) and other features in 147 children with BCR::ABL1-positive ALL (diagnosed I/2000-IV/2021, treated according to EsPhALL (n = 133) or other (n = 14) protocols), using DNA-based monitoring of BCR::ABL1 genomic breakpoint and clonal immunoglobulin/T-cell receptor gene rearrangements. Although overall prognosis of CML-like (n = 48) and typical ALL (n = 99) was similar (5-year-EFS 60% and 49%, respectively; 5-year-OS 75% and 73%, respectively), typical ALL presented more relapses while CML-like patients more often died in the first remission. Prognostic role of MRD was significant in the typical ALL (p = 0.0005 in multivariate analysis for EFS). In contrast, in CML-like patients MRD was not significant (p values > 0.2) and inapplicable for therapy adjustment. Moreover, in the typical ALL, risk-prediction could be further improved by considering initial hyperleukocytosis. Early distinguishing typical BCR::ABL1-positive ALL and CML-like patients is essential to enable optimal treatment approach in upcoming protocols. For the typical ALL, tyrosine-kinase inhibitors and concurrent chemotherapy with risk-directed intensity should be recommended; in the CML-like disease, no relevant prognostic feature applicable for therapy tailoring was found so far., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
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19. Identification of key microRNAs as predictive biomarkers of Nilotinib response in chronic myeloid leukemia: a sub-analysis of the ENESTxtnd clinical trial.
- Author
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Yen R, Grasedieck S, Wu A, Lin H, Su J, Rothe K, Nakamoto H, Forrest DL, Eaves CJ, and Jiang X
- Subjects
- Antigens, CD34, Canada, Chronic Disease, Humans, Protein Kinase Inhibitors pharmacology, Pyrimidines, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, MicroRNAs genetics
- Abstract
Despite the effectiveness of tyrosine kinase inhibitors (TKIs) against chronic myeloid leukemia (CML), they are not usually curative as some patients develop drug-resistance or are at risk of disease relapse when treatment is discontinued. Studies have demonstrated that primitive CML cells display unique miRNA profiles in response to TKI treatment. However, the utility of miRNAs in predicting treatment response is not yet conclusive. Here, we analyzed differentially expressed miRNAs in CD34
+ CML cells pre- and post-nilotinib (NL) therapy from 58 patients enrolled in the Canadian sub-analysis of the ENESTxtnd phase IIIb clinical trial which correlated with sensitivity of CD34+ cells to NL treatment in in vitro colony-forming cell (CFC) assays. We performed Cox Proportional Hazard (CoxPH) analysis and applied machine learning algorithms to generate multivariate miRNA panels which can predict NL response at treatment-naïve or post-treatment time points. We demonstrated that a combination of miR-145 and miR-708 are effective predictors of NL response in treatment-naïve patients whereas miR-150 and miR-185 were significant classifiers at 1-month and 3-month post-NL therapy. Interestingly, incorporation of NL-CFC output in these panels enhanced predictive performance. Thus, this novel predictive model may be developed into a prognostic tool for use in the clinic., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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20. Predictive scoring systems for molecular responses in persons with chronic phase chronic myeloid leukemia receiving initial imatinib therapy.
- Author
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Zhang XS, Gale RP, Li ZY, Zhang MY, Huang XJ, and Jiang Q
- Subjects
- Humans, Imatinib Mesylate therapeutic use, Male, Protein Kinase Inhibitors therapeutic use, Treatment Outcome, Antineoplastic Agents therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myeloid, Chronic-Phase drug therapy, Leukemia, Myeloid, Chronic-Phase genetics
- Abstract
It is vital for physicians and persons with chronic myeloid leukemia (CML) to accurately predict the likelihood of achieving a major molecular response (MMR) and a deep molecular response (DMR; at least MR
4 ) at the start of imatinib-therapy, which could help in decision making of treatment goals and strategies. To answer this question, we interrogated data from 1369 consecutive subjects with chronic phase CML receiving initial imatinib-therapy to identify predictive co-variates. Subjects were randomly-assigned to training (n = 913) and validation (n = 456) datasets. Male sex, higher WBC concentration, lower haemoglobin concentration, higher percentage blood blasts and larger spleen size were significantly-associated with lower cumulative incidences of MMR and MR4 in training dataset. Using Fine-Gray model, we developed the predictive scoring systems for MMR and MR4 which classified subjects into the low-, intermediate- and high-risk cohorts with significantly-different cumulative incidences of MMR and MR4 with good predictive discrimination and accuracy in training and validation cohorts with high area under the receiver-operator characteristic curve (AUROC) values. These data may help physicians decide appropriateness of initial imatinib therapy., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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21. Impact of BCR::ABL1 transcript type on RT-qPCR amplification performance and molecular response to therapy.
- Author
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Salmon M, White HE, Zizkova H, Gottschalk A, Motlova E, Cerveira N, Colomer D, Coriu D, Franke GN, Gottardi E, Izzo B, Jurcek T, Lion T, Schäfer V, Venturi C, Vigneri P, Zawada M, Zuna J, Hovorkova L, Koblihova J, Klamova H, Markova MS, Srbova D, Benesova A, Polivkova V, Zackova D, Mayer J, Roeder I, Glauche I, Ernst T, Hochhaus A, Polakova KM, and Cross NCP
- Subjects
- Humans, Imatinib Mesylate, Neoplasm, Residual genetics, Real-Time Polymerase Chain Reaction, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Abstract
Several studies have reported that chronic myeloid leukaemia (CML) patients expressing e14a2 BCR::ABL1 have a faster molecular response to therapy compared to patients expressing e13a2. To explore the reason for this difference we undertook a detailed technical comparison of the commonly used Europe Against Cancer (EAC) BCR::ABL1 reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) assay in European Treatment and Outcome Study (EUTOS) reference laboratories (n = 10). We found the amplification ratio of the e13a2 amplicon was 38% greater than e14a2 (p = 0.015), and the amplification efficiency was 2% greater (P = 0.17). This subtle difference led to measurable transcript-type dependent variation in estimates of residual disease which could be corrected by (i) taking the qPCR amplification efficiency into account, (ii) using alternative RT-qPCR approaches or (iii) droplet digital PCR (ddPCR), a technique which is relatively insensitive to differences in amplification kinetics. In CML patients, higher levels of BCR::ABL1/GUSB were identified at diagnosis for patients expressing e13a2 (n = 67) compared to e14a2 (n = 78) when analysed by RT-qPCR (P = 0.0005) but not ddPCR (P = 0.5). These data indicate that widely used RT-qPCR assays result in subtly different estimates of disease depending on BCR::ABL1 transcript type; these differences are small but may need to be considered for optimal patient management., (© 2022. The Author(s).)
- Published
- 2022
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22. Standardization of molecular monitoring of CML: results and recommendations from the European treatment and outcome study.
- Author
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White HE, Salmon M, Albano F, Andersen CSA, Balabanov S, Balatzenko G, Barbany G, Cayuela JM, Cerveira N, Cochaux P, Colomer D, Coriu D, Diamond J, Dietz C, Dulucq S, Engvall M, Franke GN, Gineikiene-Valentine E, Gniot M, Gómez-Casares MT, Gottardi E, Hayden C, Hayette S, Hedblom A, Ilea A, Izzo B, Jiménez-Velasco A, Jurcek T, Kairisto V, Langabeer SE, Lion T, Meggyesi N, Mešanović S, Mihok L, Mitterbauer-Hohendanner G, Moeckel S, Naumann N, Nibourel O, Oppliger Leibundgut E, Panayiotidis P, Podgornik H, Pott C, Rapado I, Rose SJ, Schäfer V, Touloumenidou T, Veigaard C, Venniker-Punt B, Venturi C, Vigneri P, Vorkinn I, Wilkinson E, Zadro R, Zawada M, Zizkova H, Müller MC, Saussele S, Ernst T, Machova Polakova K, Hochhaus A, and Cross NCP
- Subjects
- Fusion Proteins, bcr-abl genetics, Humans, Reference Standards, Treatment Outcome, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Abstract
Standardized monitoring of BCR::ABL1 mRNA levels is essential for the management of chronic myeloid leukemia (CML) patients. From 2016 to 2021 the European Treatment and Outcome Study for CML (EUTOS) explored the use of secondary, lyophilized cell-based BCR::ABL1 reference panels traceable to the World Health Organization primary reference material to standardize and validate local laboratory tests. Panels were used to assign and validate conversion factors (CFs) to the International Scale and assess the ability of laboratories to assess deep molecular response (DMR). The study also explored aspects of internal quality control. The percentage of EUTOS reference laboratories (n = 50) with CFs validated as optimal or satisfactory increased from 67.5% to 97.6% and 36.4% to 91.7% for ABL1 and GUSB, respectively, during the study period and 98% of laboratories were able to detect MR
4.5 in most samples. Laboratories with unvalidated CFs had a higher coefficient of variation for BCR::ABL1IS and some laboratories had a limit of blank greater than zero which could affect the accurate reporting of DMR. Our study indicates that secondary reference panels can be used effectively to obtain and validate CFs in a manner equivalent to sample exchange and can also be used to monitor additional aspects of quality assurance., (© 2022. The Author(s).)- Published
- 2022
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23. Validation and refinement of a RUNX1 mutation-associated gene expression signature in blast crisis chronic myeloid leukemia.
- Author
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Lee KL, Ko TK, Saw NYL, Javed A, Hillmer AM, Chuah C, Krishnan V, and Ong ST
- Subjects
- Gene Expression Regulation, Leukemic, Humans, Mutation, Transcriptome, Blast Crisis genetics, Core Binding Factor Alpha 2 Subunit genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Published
- 2022
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- View/download PDF
24. Spred1 deficit promotes treatment resistance and transformation of chronic phase CML.
- Author
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Qiao J, Liang C, Zhao D, Nguyen LXT, Chen F, Suo S, Hoang DH, Pellicano F, Rodriguez IR, Elhajmoussa Y, Ghoda L, Yoshimura A, Stein AS, Ali H, Koller P, Perrotti D, Copland M, Han A, Zhang BA, and Marcucci G
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Cell Transformation, Neoplastic drug effects, Cell Transformation, Neoplastic metabolism, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells metabolism, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Protein Kinase Inhibitors pharmacology, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Signal Transducing physiology, Cell Transformation, Neoplastic pathology, Drug Resistance, Neoplasm, Hematopoietic Stem Cells pathology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Neoplastic Stem Cells pathology
- Abstract
Spred1 is highly expressed in normal hematopoietic stem cells (HSCs). Lack of Spred1 function has been associated with aberrant hematopoiesis and acute leukemias. In chronic myelogenous leukemia (CML), Spred1 is reduced in patients with accelerated phase (AP) or blast crisis (BC) CML, thereby suggesting that deficit of this protein may contribute to disease transformation. In fact, Spred1 knockout (KO) in SCLtTA/BCR-ABL CML mice either globally, or restricted to hematopoietic cells (i.e., HSCs) or to endothelial cells (ECs), led to transformation of chronic phase (CP) CML into AP/BC CML. Upon BCR-ABL induction, all three Spred1 KO CML models showed AP/BC features. However, compared with global Spred1 KO, the AP/BC phenotypes of HSC-Spred1 KO and EC-Spred1 KO CML models were attenuated, suggesting a concurrent contribution of Spred1 deficit in multiple compartments of the leukemic bone marrow niche to the CML transformation. Spred1 KO, regardless if occurred in HSCs or in ECs, increased miR-126 in LSKs (Lin
- Sca-1+ c-Kit+ ), a population enriched in leukemic stem cells (LSCs), resulting in expansion of LSCs, likely through hyperactivation of the MAPK/ERK pathway that augmented Bcl-2 expression and stability. This ultimately led to enhancement of Bcl-2-dependent oxidative phosphorylation that supported homeostasis, survival and activity of LSCs and drove AP/BC transformation., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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25. Metabolic alterations mediated by STAT3 promotes drug persistence in CML.
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Patel SB, Nemkov T, Stefanoni D, Benavides GA, Bassal MA, Crown BL, Matkins VR, Camacho V, Kuznetsova V, Hoang AT, Tenen DE, Wolock SL, Park J, Ying L, Yue Z, Chen JY, Yang H, Tenen DG, Ferrell PB, Lu R, Darley-Usmar V, D'Alessandro A, Bhatia R, and Welner RS
- Subjects
- Animals, Apoptosis, Female, Glycolysis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Male, Mice, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Protein Kinase Inhibitors pharmacology, STAT3 Transcription Factor genetics, Drug Resistance, Neoplasm, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Metabolome, Neoplastic Stem Cells drug effects, STAT3 Transcription Factor metabolism, Small Molecule Libraries pharmacology, Transcriptome
- Abstract
Leukemic stem cells (LSCs) can acquire non-mutational resistance following drug treatment leading to therapeutic failure and relapse. However, oncogene-independent mechanisms of drug persistence in LSCs are incompletely understood, which is the primary focus of this study. We integrated proteomics, transcriptomics, and metabolomics to determine the contribution of STAT3 in promoting metabolic changes in tyrosine kinase inhibitor (TKI) persistent chronic myeloid leukemia (CML) cells. Proteomic and transcriptional differences in TKI persistent CML cells revealed BCR-ABL-independent STAT3 activation in these cells. While knockout of STAT3 inhibited the CML cells from developing drug-persistence, inhibition of STAT3 using a small molecule inhibitor sensitized the persistent CML cells to TKI treatment. Interestingly, given the role of phosphorylated STAT3 as a transcription factor, it localized uniquely to genes regulating metabolic pathways in the TKI-persistent CML stem and progenitor cells. Subsequently, we observed that STAT3 dysregulated mitochondrial metabolism forcing the TKI-persistent CML cells to depend on glycolysis, unlike TKI-sensitive CML cells, which are more reliant on oxidative phosphorylation. Finally, targeting pyruvate kinase M2, a rate-limiting glycolytic enzyme, specifically eradicated the TKI-persistent CML cells. By exploring the role of STAT3 in altering metabolism, we provide critical insight into identifying potential therapeutic targets for eliminating TKI-persistent LSCs., (© 2021. The Author(s).)
- Published
- 2021
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26. Sensitivity and reliability of DNA-based mutation analysis by allele-specific digital PCR to follow resistant BCR-ABL1-positive cells.
- Author
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Polivkova V, Benesova A, Zizkova H, Koblihova J, Curik N, Motlova E, Klamova H, Salek C, and Machova Polakova K
- Subjects
- Alleles, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Prognosis, DNA Mutational Analysis methods, Drug Resistance, Neoplasm genetics, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Mutation, Polymerase Chain Reaction methods, Protein Kinase Inhibitors pharmacology
- Published
- 2021
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27. Molecular status 36 months after TKI discontinuation in CML is highly predictive for subsequent loss of MMR-final report from AFTER-SKI.
- Author
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Richter J, Lübking A, Söderlund S, Lotfi K, Markevärn B, Själander A, Stenke L, Deneberg S, Ahlstrand E, Myhr-Eriksson K, Panayiotidis P, Gedde-Dahl T, Žáčková D, Mayer J, Olsson-Strömberg U, Mahon FX, Saussele S, Hjorth-Hansen H, and Koskenvesa P
- Subjects
- Europe epidemiology, Fusion Proteins, bcr-abl genetics, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Neoplasm Recurrence, Local chemically induced, Neoplasm Recurrence, Local epidemiology, Prognosis, Remission Induction, Time Factors, Clinical Trials as Topic methods, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Neoplasm Recurrence, Local diagnosis, Protein Kinase Inhibitors adverse effects, Withholding Treatment statistics & numerical data
- Published
- 2021
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28. Why chronic myeloid leukaemia cannot be cured by tyrosine kinase-inhibitors.
- Author
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Baccarani M and Gale RP
- Subjects
- Fusion Proteins, bcr-abl antagonists & inhibitors, Fusion Proteins, bcr-abl metabolism, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Molecular Targeted Therapy standards, Protein Kinase Inhibitors therapeutic use
- Published
- 2021
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29. Characterization of p190-Bcr-Abl chronic myeloid leukemia reveals specific signaling pathways and therapeutic targets.
- Author
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Adnan-Awad S, Kim D, Hohtari H, Javarappa KK, Brandstoetter T, Mayer I, Potdar S, Heckman CA, Kytölä S, Porkka K, Doma E, Sexl V, Kankainen M, and Mustjoki S
- Subjects
- Aged, Aged, 80 and over, Animals, Cell Line, Tumor, Female, Gene Expression Profiling methods, Glucocorticoids genetics, Humans, Male, Mice, Middle Aged, Oncogenes genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Proteomics methods, Transcription, Genetic genetics, Up-Regulation genetics, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Signal Transduction genetics
- Abstract
The oncogenic protein Bcr-Abl has two major isoforms, p190
Bcr-Abl and p210Bcr-Abl . While p210Bcr-Abl is the hallmark of chronic myeloid leukemia (CML), p190Bcr-Abl occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) patients. In CML, p190Bcr-Abl occurs in a minority of patients associating with distinct hematological features and inferior outcomes, yet the pathogenic role of p190Bcr-Abl and potential targeting therapies are largely uncharacterized. We employed next generation sequencing, phospho-proteomic profiling, and drug sensitivity testing to characterize p190Bcr-Abl in CML and hematopoietic progenitor cell line models (Ba/f3 and HPC-LSK). p190Bcr-Abl CML patients demonstrated poor response to imatinib and frequent mutations in epigenetic modifiers genes. In contrast with p210Bcr-Abl , p190Bcr-Abl exhibited specific transcriptional upregulation of interferon, interleukin-1 receptor, and P53 signaling pathways, associated with hyperphosphorylation of relevant signaling molecules including JAK1/STAT1 and PAK1 in addition to Src hyperphosphorylation. Comparable to p190Bcr-Abl CML patients, p190Bcr-Abl cell lines demonstrated similar transcriptional and phospho-signaling signatures. With the drug sensitivity screening we identified targeted drugs with specific activity in p190Bcr-Abl cell lines including IAP-, PAK1-, and Src inhibitors and glucocorticoids. Our results provide novel insights into the mechanisms underlying the distinct features of p190Bcr-Abl CML and promising therapeutic targets for this high-risk patient group.- Published
- 2021
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30. RUNX1 mutations in blast-phase chronic myeloid leukemia associate with distinct phenotypes, transcriptional profiles, and drug responses.
- Author
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Adnan Awad S, Dufva O, Ianevski A, Ghimire B, Koski J, Maliniemi P, Thomson D, Schreiber A, Heckman CA, Koskenvesa P, Korhonen M, Porkka K, Branford S, Aittokallio T, Kankainen M, and Mustjoki S
- Subjects
- Binding Sites, Biomarkers, Tumor, Blast Crisis diagnosis, Blast Crisis drug therapy, Cell Line, Tumor, Combined Modality Therapy, Disease Management, Disease Susceptibility, Drug Resistance, Neoplasm genetics, Flow Cytometry, Gene Deletion, Gene Editing, Humans, Ikaros Transcription Factor genetics, Immunophenotyping, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Molecular Targeted Therapy, Phenotype, Protein Binding, Signal Transduction, Exome Sequencing, Blast Crisis genetics, Core Binding Factor Alpha 2 Subunit genetics, Mutation, Transcriptome
- Abstract
Blast-phase chronic myeloid leukemia (BP-CML) is associated with additional chromosomal aberrations, RUNX1 mutations being one of the most common. Tyrosine kinase inhibitor therapy has only limited efficacy in BP-CML, and characterization of more defined molecular subtypes is warranted in order to design better treatment modalities for this poor prognosis patient group. Using whole-exome and RNA sequencing we demonstrate that PHF6 and BCORL1 mutations, IKZF1 deletions, and AID/RAG-mediated rearrangements are enriched in RUNX1
mut BP-CML leading to typical mutational signature. On transcriptional level interferon and TNF signaling were deregulated in primary RUNX1mut CML cells and stem cell and B-lymphoid factors upregulated giving a rise to distinct phenotype. This was accompanied with the sensitivity of RUNX1mut blasts to CD19-CAR T cells in ex vivo assays. High-throughput drug sensitivity and resistance testing revealed leukemia cells from RUNX1mut patients to be highly responsive for mTOR-, BCL2-, and VEGFR inhibitors and glucocorticoids. These findings were further investigated and confirmed in CRISPR/Cas9-edited homozygous RUNX1-/- and heterozygous RUNX1-/mut BCR-ABL positive cell lines. Overall, our study provides insights into the pathogenic role of RUNX1 mutations and highlights personalized targeted therapy and CAR T-cell immunotherapy as potentially promising strategies for treating RUNX1mut BP-CML patients.- Published
- 2021
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31. Is it beneficial to use hydroxychloroquine and imatinib combination in order to achieve deeper molecular responses in patients with chronic myeloid leukemia?
- Author
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Eşkazan AE
- Subjects
- Cytogenetic Analysis, Humans, Hydroxychloroquine, Imatinib Mesylate therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myeloid, Chronic-Phase
- Published
- 2020
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32. Long: molecular tracking of CML with bilineal inv(16) myeloid and del(9) lymphoid blast crisis and durable response to CD19-directed CAR-T therapy.
- Author
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Venkataraman V, Casey KS, Onozato M, Cin PD, Nardi V, Amrein PC, Bergeron MK, Brunner AM, Fathi AT, Foster JE, Moran J, Graubert TA, Hock H, Hunnewell C, Frigault MJ, McAfee S, and Hobbs GS
- Subjects
- Blast Crisis pathology, Disease Management, Disease Susceptibility, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Male, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen immunology, Treatment Outcome, Young Adult, Antigens, CD19 immunology, Blast Crisis genetics, Immunotherapy, Adoptive methods, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Oncogene Proteins, Fusion genetics
- Published
- 2020
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- View/download PDF
33. Analysis of chronic myeloid leukaemia during deep molecular response by genomic PCR: a traffic light stratification model with impact on treatment-free remission.
- Author
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Machova Polakova K, Zizkova H, Zuna J, Motlova E, Hovorkova L, Gottschalk A, Glauche I, Koblihova J, Pecherkova P, Klamova H, Stastna Markova M, Srbova D, Benesova A, Polivkova V, Jurcek T, Zackova D, Mayer J, Ernst T, Mahon FX, Saussele S, Roeder I, Cross NCP, and Hochhaus A
- Subjects
- Adult, Aged, Female, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Male, Middle Aged, Neoplasm, Residual, RNA, Messenger analysis, Remission Induction, Withholding Treatment, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Polymerase Chain Reaction methods, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases antagonists & inhibitors
- Abstract
This work investigated patient-specific genomic BCR-ABL1 fusions as markers of measurable residual disease (MRD) in chronic myeloid leukaemia, with a focus on relevance to treatment-free remission (TFR) after achievement of deep molecular response (DMR) on tyrosine kinase inhibitor (TKI) therapy. DNA and mRNA BCR-ABL1 measurements by qPCR were compared in 2189 samples (129 patients) and by digital PCR in 1279 sample (62 patients). A high correlation was found at levels of disease above MR4, but there was a poor correlation for samples during DMR. A combination of DNA and RNA MRD measurements resulted in a better prediction of molecular relapse-free survival (MRFS) after TKI stop (n = 17) or scheduled interruption (n = 25). At 18 months after treatment cessation, patients with stopped or interrupted TKI therapy who were DNA negative/RNA negative during DMR maintenance (green group) had an MRFS of 80% and 100%, respectively, compared with those who were DNA positive/RNA negative (MRFS = 57% and 67%, respectively; yellow group) or DNA positive/RNA positive (MRFS = 20% for both cohorts; red group). Thus, we propose a "traffic light" stratification as a TFR predictor based on DNA and mRNA BCR-ABL1 measurements during DMR maintenance before TKI cessation.
- Published
- 2020
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34. SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia.
- Author
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Sinnakannu JR, Lee KL, Cheng S, Li J, Yu M, Tan SP, Ong CCH, Li H, Than H, Anczuków-Camarda O, Krainer AR, Roca X, Rozen SG, Iqbal J, Yang H, Chuah C, and Ong ST
- Subjects
- Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Bone Marrow drug effects, Bone Marrow metabolism, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Prognosis, Protein Kinase Inhibitors pharmacology, Serine-Arginine Splicing Factors genetics, Tumor Cells, Cultured, Bone Marrow pathology, Cytokines pharmacology, Drug Resistance, Neoplasm drug effects, Imatinib Mesylate pharmacology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Neoplastic Stem Cells pathology, Serine-Arginine Splicing Factors metabolism
- Abstract
Patients with chronic myeloid leukemia (CML) who are treated with tyrosine kinase inhibitors (TKIs) experience significant heterogeneity regarding depth and speed of responses. Factors intrinsic and extrinsic to CML cells contribute to response heterogeneity and TKI resistance. Among extrinsic factors, cytokine-mediated TKI resistance has been demonstrated in CML progenitors, but the underlying mechanisms remain obscure. Using RNA-sequencing, we identified differentially expressed splicing factors in primary CD34
+ chronic phase (CP) CML progenitors and controls. We found SRSF1 expression to be increased as a result of both BCR-ABL1- and cytokine-mediated signaling. SRSF1 overexpression conferred cytokine independence to untransformed hematopoietic cells and impaired imatinib sensitivity in CML cells, while SRSF1 depletion in CD34+ CP CML cells prevented the ability of extrinsic cytokines to decrease imatinib sensitivity. Mechanistically, PRKCH and PLCH1 were upregulated by elevated SRSF1 levels, and contributed to impaired imatinib sensitivity. Importantly, very high SRSF1 levels in the bone marrow of CML patients at presentation correlated with poorer clinical TKI responses. In summary, we find SRSF1 levels to be maintained in CD34+ CP CML progenitors by cytokines despite effective BCR-ABL1 inhibition, and that elevated levels promote impaired imatinib responses. Together, our data support an SRSF1/PRKCH/PLCH1 axis in contributing to cytokine-induced impaired imatinib sensitivity in CML.- Published
- 2020
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35. A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease.
- Author
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Horne GA, Stobo J, Kelly C, Mukhopadhyay A, Latif AL, Dixon-Hughes J, McMahon L, Cony-Makhoul P, Byrne J, Smith G, Koschmieder S, BrÜmmendorf TH, Schafhausen P, Gallipoli P, Thomson F, Cong W, Clark RE, Milojkovic D, Helgason GV, Foroni L, Nicolini FE, Holyoake TL, and Copland M
- Subjects
- Aged, Female, Follow-Up Studies, Humans, Hydroxychloroquine administration & dosage, Imatinib Mesylate administration & dosage, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Male, Middle Aged, Prognosis, Retrospective Studies, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytogenetic Analysis methods, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
- Abstract
In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared with IM alone in CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two patients were randomly assigned to either arm. Treatment 'successes' was the primary end point, defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end points were 24-month treatment 'successes', molecular response and progression at 12 and 24 months, comparison of IM levels, and achievement of blood HCQ levels >2000 ng/ml. At 12 months, there was no difference in 'success' rate (p = 0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p = 0.21). At 24 months, the 'success' rate was 20.8% higher with IM/HCQ (p = 0.059). No patients progressed. Seventeen serious adverse events, including four serious adverse reactions, were reported; diarrhoea occurred more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.
- Published
- 2020
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36. Lineage of measurable residual disease in patients with chronic myeloid leukemia in treatment-free remission.
- Author
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Pagani IS, Dang P, Saunders VA, Grose R, Shanmuganathan N, Kok CH, Carne L, Rwodzi Z, Watts S, McLean J, Braley J, Altamura H, Yeung DT, Branford S, Yong ASM, White DL, Hughes TP, and Ross DM
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Fusion Proteins, bcr-abl antagonists & inhibitors, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Lymphocyte Subsets drug effects, Lymphocyte Subsets metabolism, Male, Middle Aged, Neoplasm, Residual drug therapy, Neoplasm, Residual genetics, Neoplasm, Residual pathology, Prognosis, Protein Kinase Inhibitors therapeutic use, Remission Induction, Cell Lineage, Fusion Proteins, bcr-abl genetics, Imatinib Mesylate therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive immunology, Lymphocyte Subsets immunology, Neoplasm, Residual immunology
- Abstract
Approximately half of patients with chronic myeloid leukemia (CML) in sustained deep molecular response who discontinue tyrosine kinase inhibitors (TKIs) remain in treatment-free remission (TFR). Some of these patients have measurable residual disease (MRD) by BCR-ABL1 mRNA testing, and most have detectable BCR-ABL1 DNA by highly sensitive methods. We used fluorescence-activated cell sorting and BCR-ABL1 DNA PCR to investigate the lineage of residual CML cells in TFR. Twenty patients in TFR for >1 year provided blood for sorting into granulocytes, monocytes, B cells, T cells, and NK cells. MRD was identified predominantly in the lymphoid compartment and never in granulocytes. B cells were more often BCR-ABL1 positive than T cells (18 vs 11/20 patients) and at higher levels (median 10
-4.9 vs 10-5.7 ; P = 0.014). In 13 CML patients studied at diagnosis lymphocytes expressing BCR-ABL1 mRNA comprised a small proportion of total leukocytes. These data improve our understanding of TFR biology, since it is now clear that MRD in the blood of TFR patients need not imply the persistence of multipotent CML cells. Lineage-specific assessment of MRD could be explored as a means to improve the prediction of TFR.- Published
- 2020
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37. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia.
- Author
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Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, Clark RE, Cortes JE, Deininger MW, Guilhot F, Hjorth-Hansen H, Hughes TP, Janssen JJWM, Kantarjian HM, Kim DW, Larson RA, Lipton JH, Mahon FX, Mayer J, Nicolini F, Niederwieser D, Pane F, Radich JP, Rea D, Richter J, Rosti G, Rousselot P, Saglio G, Saußele S, Soverini S, Steegmann JL, Turkina A, Zaritskey A, and Hehlmann R
- Subjects
- Aniline Compounds therapeutic use, Clinical Decision-Making, Consensus Development Conferences as Topic, Dasatinib therapeutic use, Disease Management, Fusion Proteins, bcr-abl genetics, Fusion Proteins, bcr-abl metabolism, Gene Expression, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Life Expectancy trends, Monitoring, Physiologic, Nitriles therapeutic use, Pyrimidines therapeutic use, Quality of Life, Quinolines therapeutic use, Survival Analysis, Antineoplastic Agents therapeutic use, Fusion Proteins, bcr-abl antagonists & inhibitors, Imatinib Mesylate therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Protein Kinase Inhibitors therapeutic use
- Abstract
The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.
- Published
- 2020
- Full Text
- View/download PDF
38. In Ph+BCR-ABL1 P210+ acute lymphoblastic leukemia the e13a2 (B2A2) transcript is prevalent.
- Author
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Baccarani M, Iacobucci I, Chiaretti S, Foà' R, Balasubramanian P, Paietta E, Foroni L, Jeromin S, Izzo B, Spinelli O, Varma N, Menif S, Terragna C, Seth T, Bidet A, Coriu D, Lunghi F, Mayer J, Scappini B, Langabeer S, Maier J, Burt E, Candoni A, Albano F, Luppi M, Zupan I, Lion T, Zadro R, di Raimondo F, Poopak B, Rege-Cambrin G, Annunziata M, Ayala A, Salinas-Viedma V, Ines Prado A, Milner B, Galimberti S, Janssen J, Polli V, Comba L, Borsellino B, Annibali O, Crugnola M, and Passamonti F
- Subjects
- Adolescent, Adult, Age Factors, Aged, B-Lymphocytes immunology, Child, Female, Humans, Male, Middle Aged, Proto-Oncogene Proteins c-abl immunology, Young Adult, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Published
- 2020
- Full Text
- View/download PDF
39. Chronic myeloid leukemia: the concepts of resistance and persistence and the relationship with the BCR-ABL1 transcript type.
- Author
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Baccarani M, Rosti G, and Soverini S
- Subjects
- Antineoplastic Agents therapeutic use, Drug Resistance, Neoplasm drug effects, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Protein Kinase Inhibitors therapeutic use, Quality of Life, Drug Resistance, Neoplasm genetics, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Abstract
Chronic myeloid leukemia is driven by a hybrid gene, BCR-ABL1, that codes for a leukemogenic tyrosine kinase (TK) protein of 210 KDa (p210
BCR-ABL1 ). Resistance to TK inhibitor (TKI) therapy occurs in relatively few patients, no more than 10%, while persistence of minimal residual disease during TKI therapy occurs in the great majority of patients. Resistance is a cause of death, persistence is compatible with a fairly normal length and quality of life, but may require lifelong treatment. The causes of resistance are heterogeneous, including the development of other genomic abnormalities or the altered expression of other genes, requiring different treatments. The causes of persistence may not be the same as those of resistance. We hypothesize that the variability in breakpoint position within the Major-breakpoint cluster region (M-bcr), resulting in two different messenger RNAs that may or may not include exon 14 of BCR (e13a2 and e14a2, respectively), and, as a consequence, in two p210BCR-ABL1 proteins that differ by 25 amino acids, may be a cause of persistence. The hypothesis is based on a critical review of the relationships between the BCR-ABL1 transcript types, the response to TKIs, the outcome of treatment, and the immune response, suggesting that the e14a2 transcript is associated with more and deeper molecular responses, hence with a higher probability of achieving treatment-free remission (TFR). Investigating this putative cause of persistence may help bringing more patients into stable TFR.- Published
- 2019
- Full Text
- View/download PDF
40. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia.
- Author
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Branford S, Kim DDH, Apperley JF, Eide CA, Mustjoki S, Ong ST, Nteliopoulos G, Ernst T, Chuah C, Gambacorti-Passerini C, Mauro MJ, Druker BJ, Kim DW, Mahon FX, Cortes J, Radich JP, Hochhaus A, and Hughes TP
- Subjects
- Genes, Neoplasm, Hematopoiesis, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive etiology, Mutation, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases antagonists & inhibitors, Repressor Proteins genetics, Risk Assessment, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Abstract
Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.
- Published
- 2019
- Full Text
- View/download PDF
41. The transcriptional regulator FUBP1 influences disease outcome in murine and human myeloid leukemia.
- Author
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Hoang VT, Verma D, Godavarthy PS, Llavona P, Steiner M, Gerlach K, Michels BE, Bohnenberger H, Wachter A, Oellerich T, Müller-Kuller U, Weissenberger E, Voutsinas JM, Oehler VG, Farin HF, Zörnig M, and Krause DS
- Subjects
- Animals, Bone Marrow Transplantation, Cell Cycle, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins genetics, Humans, Irinotecan pharmacology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Mice, Mice, Inbred C57BL, RNA-Binding Proteins antagonists & inhibitors, RNA-Binding Proteins genetics, Topoisomerase I Inhibitors pharmacology, Tumor Cells, Cultured, Apoptosis, DNA Damage, DNA-Binding Proteins metabolism, Disease Models, Animal, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Leukemia, Myeloid, Acute pathology, RNA-Binding Proteins metabolism
- Abstract
The transcriptional regulator far upstream element binding protein 1 (FUBP1) acts as an oncoprotein in solid tumor entities and plays a role in the maintenance of hematopoietic stem cells. However, its potential function in leukemia is unknown. In murine models of chronic (CML) and acute myeloid leukemia (AML) induced by BCR-ABL1 and MLL-AF9, respectively, knockdown of Fubp1 resulted in prolonged survival, decreased numbers of CML progenitor cells, decreased cell cycle activity and increased apoptosis. Knockdown of FUBP1 in CML and AML cell lines recapitulated these findings and revealed enhanced DNA damage compared to leukemia cells expressing wild type FUBP1 levels. FUBP1 was more highly expressed in human CML compared to normal bone marrow cells and its expression correlated with disease progression. In AML, higher FUBP1 expression in patient leukemia cells was observed with a trend toward correlation with shorter overall survival. Treatment of mice with AML with irinotecan, known to inhibit topoisomerase I and FUBP1, significantly prolonged survival alone or in combination with cytarabine. In summary, our data suggest that FUBP1 acts as cell cycle regulator and apoptosis inhibitor in leukemia. We demonstrated that FUBP1 might play a role in DNA repair, and its inhibition may improve outcome in leukemia patients.
- Published
- 2019
- Full Text
- View/download PDF
42. HMGCLL1 is a predictive biomarker for deep molecular response to imatinib therapy in chronic myeloid leukemia.
- Author
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Park JH, Woo YM, Youm EM, Hamad N, Won HH, Naka K, Park EJ, Park JH, Kim HJ, Kim SH, Kim HJ, Ahn JS, Sohn SK, Moon JH, Jung CW, Park S, Lipton JH, Kimura S, Kim JW, and Kim DDH
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Apoptosis, Case-Control Studies, Cell Survival, Cohort Studies, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Male, Middle Aged, Prognosis, Survival Rate, Tumor Cells, Cultured, Young Adult, Biomarkers, Tumor genetics, Drug Resistance, Neoplasm, Imatinib Mesylate therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Mutation, Oxo-Acid-Lyases genetics, Protein Kinase Inhibitors therapeutic use
- Abstract
Achieving a deep molecular response (DMR) to tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) remains challenging and at present, there is no biomarker to predict DMR in this setting. Herein, we report that an HMGCLL1 genetic variant located in 6p12.1 can be used as a predictive genetic biomarker for intrinsic sensitivity to imatinib (IM) therapy. We measured DMR rate according to HMGCLL1 variant in a discovery set of CML patients (n = 201) and successfully replicated it in a validation set (n = 270). We also investigated the functional relevance of HMGCLL1 blockade with respect to response to TKI therapy and showed that small interfering RNA mediated blockade of HMGCLL1 isoform 3 results in significant decrease in viability of BCR-ABL1-positive cells including K562, CML-T1 or BaF3 cell lines with or without ABL1 kinase domain mutations such as T315I mutation. Decreased cell viability was also demonstrated in murine CML stem cells and human hematopoietic progenitor cells. RNA sequencing showed that blockade of HMGCLL1 was associated with G0/G1 arrest and the cell cycle. In summary, the HMGCLL1 gene polymorphism is a novel genetic biomarker for intrinsic sensitivity to IM therapy in CML patients that predicts DMR in this setting.
- Published
- 2019
- Full Text
- View/download PDF
43. The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview.
- Author
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Baccarani M, Castagnetti F, Gugliotta G, Rosti G, Soverini S, Albeer A, and Pfirrmann M
- Subjects
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Global Health, Humans, Infant, Infant, Newborn, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Male, Middle Aged, Odds Ratio, Prevalence, Transcriptional Activation, Young Adult, Fusion Proteins, bcr-abl genetics, Gene Expression Regulation, Leukemic, Leukemia, Myelogenous, Chronic, BCR-ABL Positive epidemiology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Abstract
There are different BCR-ABL1 fusion genes that are translated into proteins that are different from each other, yet all leukemogenic, causing chronic myeloid leukemia (CML) or acute lymphoblastic leukemia. Their frequency has never been systematically investigated. In a series of 45503 newly diagnosed CML patients reported from 45 countries, it was found that the proportion of e13a2 (also known as b2a2) and of e14a2 (also known as b3a2), including the cases co-expressing e14a2 and e13a2, was 37.9% and 62.1%, respectively. The proportion of these two transcripts was correlated with gender, e13a2 being more frequent in males (39.2%) than in females (36.2%), was correlated with age, decreasing from 39.6% in children and adolescents down to 31.6% in patients ≥ 80 years old, and was not constant worldwide. Other, rare transcripts were reported in 666/34561 patients (1.93%). The proportion of rare transcripts was associated with gender (2.27% in females and 1.69% in males) and with age (from 1.79% in children and adolescents up to 3.84% in patients ≥ 80 years old). These data show that the differences in proportion are not by chance. This is important, as the transcript type is a variable that is suspected to be of prognostic importance for response to treatment, outcome of treatment, and rate of treatment-free remission.
- Published
- 2019
- Full Text
- View/download PDF
44. Frequent ASXL1 mutations in children and young adults with chronic myeloid leukemia.
- Author
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Ernst T, Busch M, Rinke J, Ernst J, Haferlach C, Beck JF, Hochhaus A, and Gruhn B
- Subjects
- Adolescent, Adult, Age Factors, Alleles, Biomarkers, Tumor, Child, Child, Preschool, DNA Mutational Analysis, Female, Fusion Proteins, bcr-abl genetics, High-Throughput Nucleotide Sequencing, Humans, In Situ Hybridization, Fluorescence, Infant, Infant, Newborn, Male, Young Adult, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Mutation, Repressor Proteins genetics
- Published
- 2018
- Full Text
- View/download PDF
45. SHP2 is required for BCR-ABL1-induced hematologic neoplasia.
- Author
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Gu S, Sayad A, Chan G, Yang W, Lu Z, Virtanen C, Van Etten RA, and Neel BG
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Apoptosis drug effects, Apoptosis genetics, Cell Line, Cell Proliferation drug effects, Cell Proliferation genetics, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, HEK293 Cells, Hematologic Neoplasms drug therapy, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Mice, Mice, Inbred C57BL, Myeloproliferative Disorders drug therapy, Myeloproliferative Disorders genetics, Myeloproliferative Disorders pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Protein Kinase Inhibitors pharmacology, Signal Transduction drug effects, Signal Transduction genetics, src Homology Domains genetics, Fusion Proteins, bcr-abl genetics, Hematologic Neoplasms genetics, Hematologic Neoplasms pathology, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics
- Abstract
BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph
+ ) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation models for CML and BCR-ABL1+ B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+ B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, are essential for BCR-ABL1+ , but not WT, pre-B-cell proliferation. The mitogen-activated protein kinase kinase (MEK) / extracellular signal-regulated kinase (ERK) pathway is regulated by SHP2 in WT and BCR-ABL1+ pre-B cells, but is only required for the proliferation of BCR-ABL1+ cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+ pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+ and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.- Published
- 2018
- Full Text
- View/download PDF
46. Mechanisms of resistance to the BCR-ABL1 allosteric inhibitor asciminib.
- Author
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Qiang W, Antelope O, Zabriskie MS, Pomicter AD, Vellore NA, Szankasi P, Rea D, Cayuela JM, Kelley TW, Deininger MW, and O'Hare T
- Subjects
- Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation genetics, Drug Resistance, Neoplasm genetics, Fusion Proteins, bcr-abl genetics, Humans, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Niacinamide pharmacology, Drug Resistance, Neoplasm drug effects, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Niacinamide analogs & derivatives, Protein Kinase Inhibitors pharmacology, Pyrazoles pharmacology
- Published
- 2017
- Full Text
- View/download PDF
47. Cytogenetically cryptic ZMYM2-FLT3 and DIAPH1-PDGFRB gene fusions in myeloid neoplasms with eosinophilia.
- Author
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Jawhar M, Naumann N, Knut M, Score J, Ghazzawi M, Schneider B, Kreuzer KA, Hallek M, Drexler HG, Chacko J, Wallis L, Fabarius A, Metzgeroth G, Hofmann WK, Chase A, Tapper W, Reiter A, and Cross NCP
- Subjects
- Female, Formins, Humans, Male, Middle Aged, Myeloproliferative Disorders genetics, Protein-Tyrosine Kinases genetics, Adaptor Proteins, Signal Transducing genetics, DNA-Binding Proteins genetics, Eosinophilia genetics, Gene Fusion genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Receptor, Platelet-Derived Growth Factor beta genetics, Transcription Factors genetics, fms-Like Tyrosine Kinase 3 genetics
- Published
- 2017
- Full Text
- View/download PDF
48. No increased prevalence of malignancies among first-degree relatives of 800 patients with chronic myeloid leukemia: a population-based study in Sweden.
- Author
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Gunnarsson N, Höglund M, Stenke L, Sandin F, Björkholm M, Dreimane A, Lambe M, Markevärn B, Olsson-Strömberg U, Wadenvik H, Richter J, and Själander A
- Subjects
- Case-Control Studies, Female, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Male, Prevalence, Registries, Sweden epidemiology, Family, Leukemia, Myelogenous, Chronic, BCR-ABL Positive epidemiology, Population Surveillance
- Published
- 2017
- Full Text
- View/download PDF
49. Cytogenetic landscape and impact in blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy.
- Author
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Chen Z, Shao C, Wang W, Zuo Z, Mou X, Hu SJ, DiGiuseppe JA, Zu Y, Medeiros LJ, and Hu S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Blast Crisis drug therapy, Blast Crisis mortality, Bone Marrow pathology, Chromosomes, Human, Pair 3, Female, Fusion Proteins, bcr-abl genetics, Humans, Immunophenotyping, In Situ Hybridization, Fluorescence, Karyotyping, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Male, Middle Aged, Molecular Targeted Therapy, Mutation, Prognosis, Protein Kinase Inhibitors therapeutic use, Transcription, Genetic, Translocation, Genetic, Treatment Outcome, Young Adult, Blast Crisis diagnosis, Blast Crisis genetics, Chromosome Aberrations, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Abstract
The landscape of additional chromosomal alterations (ACAs) and their impact in chronic myeloid leukemia, blast phase (CML-BP) treated with tyrosine kinase inhibitors (TKIs) have not been well studied. Here, we investigated a cohort of 354 CML-BP patients treated with TKIs. We identified +8, an extra Philadelphia chromosome (Ph), 3q26.2 rearrangement, -7 and isochromosome 17q (i(17q)) as the major-route changes with a frequency of over 10%. In addition, +21 and +19 had a frequency of over 5%. These ACAs demonstrated lineage specificity: +8, 3q26.2 rearrangement, i(17q) and +19 were significantly more common in myeloid BP, and -7 more common in lymphoid BP; +Ph and +21 were equally distributed between two groups. Pearson correlation analysis revealed clustering of common ACAs into two groups: 3q26.2 rearrangement, -7 and i(17q) formed one group, and other ACAs formed another group. The grouping correlated with risk stratification of ACAs in CML, chronic phase. Despite the overall negative prognostic impact of ACAs, stratification of ACAs into major vs minor-route changes provided no prognostic relevance in CML-BP. The emergence of 3q26.2 rearrangement as a major-route change in the TKI era correlated with a high frequency of ABL1 mutations, supporting a role for TKI resistance in the changing cytogenetic landscape in CML-BP.
- Published
- 2017
- Full Text
- View/download PDF
50. Rapid conversion of chronic myeloid leukemia to chronic myelomonocytic leukemia in a patient on imatinib therapy.
- Author
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Khorashad JS, Tantravahi SK, Yan D, Mason CC, Qiao Y, Eiring AM, Gligorich K, Hein T, Pomicter AD, Reid AG, Kelley TW, Marth GT, O'Hare T, and Deininger MW
- Subjects
- Aged, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Leukemia, Myelomonocytic, Chronic genetics, Leukemia, Myelomonocytic, Chronic pathology, Male, Mutation, Antineoplastic Agents therapeutic use, Imatinib Mesylate therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelomonocytic, Chronic drug therapy
- Published
- 2016
- Full Text
- View/download PDF
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