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© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/., T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric cancer. Amongst the wide array of driver mutations, 10% of T-ALL patients display gain-of-function mutations in the IL-7 receptor α chain (IL-7Rα, encoded by IL7R), which occur in different molecular subtypes of this disease. However, it is still unclear whether IL-7R mutational activation is sufficient to transform T-cell precursors. Also, which genes cooperate with IL7R to drive leukemogenesis remain poorly defined. Here, we demonstrate that mutant IL7R alone is capable of inducing T-ALL with long-latency in stable transgenic zebrafish and transformation is associated with MYC transcriptional activation. Additionally, we find that mutant IL7R collaborates with Myc to induce early onset T-ALL in transgenic zebrafish, supporting a model where these pathways collaborate to drive leukemogenesis. T-ALLs co-expressing mutant IL7R and Myc activate STAT5 and AKT pathways, harbor reduced numbers of apoptotic cells and remake tumors in transplanted zebrafish faster than T-ALLs expressing Myc alone. Moreover, limiting-dilution cell transplantation experiments reveal that activated IL-7R signaling increases the overall frequency of leukemia propagating cells. Our work highlights a synergy between mutant IL7R and Myc in inducing T-ALL and demonstrates that mutant IL7R enriches for leukemia propagating potential., This work was supported by NIH grant R01CA211734 (DML), the MGH Research Scholar Award (DML), the ERC consolidator CoG-648455 and proof-of-concept PoC-862545 grants from the European Research Council, under the European Union’s Horizon 2020 research and innovation programme (JTB), and the FCT grants FAPESP/ 20015/2014, PTDC/MEC-HEM/31588/2017 and PTDC/MEC-ONC/4606/2021 (JTB)

Achievement of a negative minimal residual disease state after hypomethylating agent therapy in older patients with AML reduces the risk of relapse

Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is

Internal tandem duplication (ITD) mutation in Fms-like tyrosine kinase 3 gene (FLT3/ITD) represents an unfavorable genetic change in acute myeloid leukemia (AML) and is associated with poor prognosis. Metabolic alterations have been involved in tumor progression and attracted interest as a target for therapeutic intervention. However, few studies analyzed the adaptations of cellular metabolism in the context of FLT3/ITD mutation. Here, we report that FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity. Inhibition of glycolysis preferentially causes severe ATP depletion and massive cell death in FLT3/ITD leukemia cells. Glycolytic inhibitors significantly enhances the cytotoxicity induced by FLT3 tyrosine kinase inhibitor sorafenib. Importantly, such combination provides substantial therapeutic benefit in a murine model bearing FLT3/ITD leukemia. Our study suggests that FLT3/ITD mutation promotes Warburg effect, and such metabolic alteration can be exploited to develop effective therapeutic strategy for treatment of AML with FLT3/ITD mutation via metabolic intervention.

While therapy-related (t)-myelodysplastic syndromes (MDS) have worse outcomes than de novo MDS (d-MDS), some t-MDS patients have an indolent course. Most MDS prognostic models excluded t-MDS patients during development. The performances of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Global Prognostic System (MPSS), WHO Prognostic Scoring System (WPSS) and t-MDS Prognostic System (TPSS) were compared among patients with t-MDS. Akaike information criteria (AIC) assessed the relative goodness of fit of the models. We identified 370 t-MDS patients (19%) among 1950 MDS patients. Prior therapy included chemotherapy alone (48%), chemoradiation (31%), and radiation alone in 21%. Median survival for t-MDS patients was significantly shorter than for d-MDS (19 vs 46 months, P

Established prognostic tools in patients with myelodysplastic syndromes (MDS) were largely derived from untreated patient cohorts. Although azanucleosides are standard therapies for higher-risk (HR)-MDS, the relative prognostic performance of existing prognostic tools among patients with HR-MDS receiving azanucleoside therapy is unknown. In the MDS Clinical Research Consortium database, we compared the prognostic utility of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Prognostic Scoring System (MDAPSS), World Health Organization-based Prognostic Scoring System (WPSS) and the French Prognostic Scoring System (FPSS) among 632 patients who presented with HR-MDS and were treated with azanucleosides as the first-line therapy. Median follow-up from diagnosis was 15.7 months. No prognostic tool predicted the probability of achieving an objective response. Nonetheless, all five tools were associated with overall survival (OS, P = 0.025 for the IPSS, P = 0.011 for WPSS and P < 0.001 for the other three tools). The corrected Akaike Information Criteria, which were used to compare OS with the different prognostic scoring systems as covariates (lower is better) were 4138 (MDAPSS), 4156 (FPSS), 4196 (IPSS-R), 4186 (WPSS) and 4196 (IPSS). Patients in the highest-risk groups of the prognostic tools had a median OS from diagnosis of 11 – 16 months and should be considered for up-front transplantation or experimental approaches.

CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.

Comprehensive analysis of factors impacting risks and outcomes of therapy-related myeloid neoplasms following breast cancer treatment

Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal hematologic malignancies that are characterized by defective bone marrow (BM) hematopoiesis and by the occurrence of intramedullary apoptosis. During the past decade, the identification of key genetic and epigenetic alterations in patients has improved our understanding of the pathophysiology of this disease. However, the specific molecular mechanisms leading to the pathogenesis of MDS have largely remained obscure. Recently, essential evidence supporting the direct role of innate immune abnormalities in MDS has been obtained, including the identification of multiple key regulators that are overexpressed or constitutively activated in BM hematopoietic stem and progenitor cells. Mounting experimental results indicate that the dysregulation of these molecules leads to abnormal hematopoiesis, unbalanced cell death and proliferation in patients' BM, and has an important role in the pathogenesis of MDS. Furthermore, there is compelling evidence that the deregulation of innate immune and inflammatory signaling also affects other cells from the immune system and the BM microenvironment, which establish aberrant associations with hematopoietic precursors and contribute to the MDS phenotype. Therefore, the deregulation of innate immune and inflammatory signaling should be considered as one of the driving forces in the pathogenesis of MDS. In this article, we review and update the advances in this field, summarizing the results from the most recent studies and discussing their clinical implications.

Most clinical trials exclude patients with poor performance or comorbidities. To study whether patients with these characteristics can be treated within a clinical trial, we conducted a study for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with poor performance, organ dysfunction or comorbidities. Primary endpoint was 60-day survival. Study included stopping rules for survival and response. Treatment consisted on a combination of azacitidine and vorinostat. Thirty patients (16 with MDS, 14 with AML) were enrolled. Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. No stopping rules were met. Main adverse events (AEs) were grades 1 and 2 gastrointestinal toxicities. In view of these results, we expanded the study and treated 79 additional patients: 27 with azacitidine (AZA) and 52 with azacitidine and vorinostat (AZA+V). Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rate was 79% (AZA=67%, AZA+V=85%, P=0.07). Median overall survival was 7.6 months (4.5-10.7). Median event-free survival was 4.5 months (3.5-5.6). Main AEs included grades 1 and 2 gastrointestinal toxicities. Our results suggest this subset of patients can be safely treated within clinical trials and derive clinical benefit. Relaxation of standard exclusion criteria may increase the pool of patients likely to benefit from therapy.

Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy

Application of the International Prognostic Scoring System-Revised in therapy-related myelodysplastic syndromes and oligoblastic acute myeloid leukemia

Randomized, dose-escalation study of the p38α MAPK inhibitor SCIO-469 in patients with myelodysplastic syndrome

Sorafenib is a multikinase inhibitor and a potent FLT3 inhibitor that inhibits tumor growth and angiogenesis by inhibiting intracellular Raf kinases and cell surface kinase receptors such as VEGFR, PDGFR-beta, cKIT, and FLT-3.1 It has been approved by the U.S. Food and Drug Administration for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma at a standard dose of 400 mg twice daily. The antileukemic activity of sorafenib has been evaluated in preclinical models and a number of recently reported clinical trials.2 In a phase I/II study, combination therapy with sorafenib, cytarabine, and idarubicin in younger patients with AML was able to induce a high complete response (CR) rate in those with FLT3 mutations and a 1-year probability of survival of 74%.3 We here report long-term outcome for adults with newly diagnosed AML who were treated with a combination of sorafenib, cytarabine, and idarubicin. Details of the patient population and the treatment regimen have been previously published.3 Survival curves were plotted by the Kaplan-Meier method and compared using the log-rank test. Differences in subgroups by different covariates were evaluated using the x2 test for nominal values and Fisher's exact test for continuous variables. Between February 1, 2008, and March 31, 2010, 62 patients with previously untreated AML were enrolled in this study. Patient characteristics are summarized in Table 1a. The median age of the patients was 53 years (range, 18 to 66 years); 12 were older than or equal to 60 years. Twenty-three had FLT3 mutations, including 17 with FLT3-ITD (10 with low mutation burden), 4 with D835 mutation, and 2 with both mutations; 11 patients had antecedent hematologic disorder and 10 had unfavorable cytogenetics. Herein, we will refer to the patients as FLT3-ITD-positive or negative including the 4 patients with sole D835 mutation in the latter group and the 2 with both mutations in the former group. Table 1a Patient characteristics The median white blood cell count (WBC) at presentation was 7.25 × 109/L (range, 0.6 to 228.5 × 109/L). Eight patients were FLT3-ITD–positive/nucleophosmin-1 (NPM1)–negative. The median age of patients with FLT3-ITD mutation was 52 years (range, 20 to 66 years); one had adverse and 18 had intermediate cytogenetics (17 with normal karyotype) based on MRC criteria. Sixty-one patients had response assessment; one patient died before response assessment could be performed. Among these, 49 (79%) achieved CR, and 5 (8%) CRp. Seven (11%) patients were non-responders. Among the 54 responders, 51 patients received consolidation and maintenance courses; 3 proceeded to allogeneic stem cell transplant straight after induction. Patients with FLT3-ITD were more likely to achieve a CR/CRp than were patients without FLT3-ITD [18 of 19 patients (95%) vs. 36 of 43 (84%), respectively (P = 0.23)] (Table 1b). Seventeen FLT3-ITD patients achieved CR and one had CRp, three FLT3-D835 patients achieved a CR and one had CRp, and 32 of 43 patients without FLT3-ITD achieved a CR and four had CRp; one died at induction, and six were resistant to therapy. CR was achieved after one induction cycle in 44 patients and after two induction cycles in five patients. Sixteen patients with the FLT3-ITD mutation achieved CR/CRp after one induction cycle, and two achieved it after two cycles. Altogether, sixteen patients proceeded to allogeneic stem-cell transplantation in first CR/CRp, including nine with a FLT3 mutation (six with FLT3-ITD, three with FLT3-D835). To date, 35 (65%) of the responders have experienced relapse including 11 of 18 patients (61%) with FLT3-ITD and 24 of 36 (67%) without FLT3-ITD (P = 0.69); 33 patients received salvage therapy: 2 died while receiving first salvage therapy, 11 achieved a second CR, 2 CRp, 1 PR and 17 had refractory disease. Ultimately 22 of these 33 patients died after their first or subsequent salvage therapies. Table 1b Response to induction according to FLT3 status With a median follow-up of 52 months (range, 2.3-62.9 months) for all patients, the median OS and DFS were 29 and 13.8 months, respectively (Figure 1a and ​and1b).1b). Figure 1c and ​and1d1d demonstrates the OS and DFS for all patients and for patients with FLT3-ITD. Among patients with FLT3-ITD who achieved CR/CRp, 11 have relapsed and 5 remain in CR; 2 patients died in CR. The median OS and DFS among the 19 patients with FLT3-ITD was 15.5 and 9.9 months, respectively (Figure 1c and ​and1d1d). Figure 1 (a) OS for all patients; (b) DFS for all patients; (c) OS according to FLT3-ITD status; (d) DFS according to FLT3-ITD status. Hematopoietic stem cell transplantation was performed in first CR in 16 of 54 patients who achieved a CR/CRp (30%); six of the 16 relapsed and 7 died following the SCT. The 3-year disease-free survival (DFS) rate (in 54 patients achieving CR/CRp) was 34%; the 3-year OS rate for all patients was 48% (Figure 1a and ​and1b1b). The regimen was generally well tolerated, the adverse events being those expected in patients receiving induction chemotherapy with the combination of cytarabine and idarubicin. The most common grade 3 and 4 adverse events possibly associated with the addition of sorafenib to the induction regimen occurred in 15 patients and included nausea and vomiting (7), cardiac/hypertension (6), diarrhea (5), infections (5), hand and foot syndrome (4), liver toxicity (5), and pancreatitis (2). One patient died of massive myocardial infarction during induction; this was not considered to be related to sorafenib (Table 1c). Table 1c Toxicity Mutations in FLT3 are well-established indicators of poor prognosis in AML 4,5 and occur in approximately 20% to 30% of patients. Small-molecule FLT3 kinase inhibitors have been developed with different efficacies against FLT3-mutant cell lines. They also have been evaluated in FLT3-ITD+ primary leukemia cells, alone or in combination with cytarabine and anthracyclines such as idarubicin. 6,7,8,9 This study reports on the long-term follow-up of patients with newly diagnosed AML who received upfront treatment consisting of sorafenib combined with cytarabine and idarubicin. Nineteen patients had the FLT3-ITD mutation. The response rates (CR and CRp) for patients with FLT3-ITD were higher than that for patients without FLT3-ITD including those with FLT3-D835 mutants and those with wild-type FLT3 (18/19 patients [95%] vs. 36/43 [83%], respectively) although this was not statistically significant (P = 0.23). Similarly, there was no significant difference in OS or DFS when comparing patients with and without FLT3-ITD (Figure 1c and ​and1d).1d). This is in contrast to previous studies reporting significantly shorter DFS and OS for patients with FLT3-ITD and can potentially be attributable to the addition of sorafenib to the regimen. This may be due to the possible increased likelihood of the patients to be able to undergo an allogeneic stem cell transplant as a result of the addition of sorafenib. We also analyzed the outcomes censoring patients at the time of allogeneic stem cell transplant (n=16) and found no significant difference between the groups' outcomes (data not shown). In this study, the sorafenib containing induction regimen produced a high response rate but was associated with relapse in the majority of the patients. Man et al. 10 reported activation of alternative survival pathways in sorafenib-resistant leukemic clones. In their study, 12 of 13 patients with AML and FLT3-ITD responded to treatment with sorafenib monotherapy but nine lost their response at a median of 72 days. We had a similar high response rate in this study but the median DFS was significantly longer at 9.9 months suggesting a potential benefit for combining sorafenib with chemotherapy, especially that overall, the treatment was well tolerated with limited grade 3 and 4 toxicity. A recent report, however, suggested that the addition of sorafenib to standard cytarabine and daunorubicin induction regimen did not improve EFS or OS and was associated with increased toxicity during induction.11 However, the patients treated in that study were older than 60 which may account for the higher incidence of toxicity. Our study is limited due to the inability to discern the impact of other interventions such as allogeneic stem cell transplant, related to its non-randomized design and limited patient numbers. Rollig and colleagues have reported preliminary results of SORAML trial in which patients received cytarabine 100 mg/m2 for 7 days plus daunorubicin 60 mg/m2 for 3 days followed by high dose cytarabine consolidation.12 Patients were randomized to receive Sorafenib at a dose of 800 mg/day or placebo during induction and consolidation and for a 12 months maintenance period after the end of consolidation. Among the 276 patients randomized, 264 were evaluable for event-free survival (EFS), 132 in each arm.12 Patient and disease characteristics were similar between the two arms, with the FLT3-ITD incidence of 16%. The CR rates were 56% and 60% in the placebo and sorafenib arms, respectively (p=0.62). With a median follow-up of 18 months, the median EFS was 12.2 months in the placebo arm and was not reached in the sorafenib arm; the 2-year OS was 66% versus 72% in placebo and sorafenib arms, respectively (p=0.37). Although there was an increased risk of hepatotoxicity and bleeding events in the sorafenib arm, the authors concluded that the addition of sorafenib was associated with a prolongation of EFS which was most marked in the patients with FLT3-ITD.12 The eventual result of this study will better clarify the potential role of sorafenib in the treatment of patients with AML and FLT3-ITD.

This cooperative study assessed prognostic factors for overall survival (OS) and risk of transformation to acute myeloid leukemia (AML) in 541 patients with de novo myelodysplastic syndrome (MDS) and deletion 5q. Additional chromosomal abnormalities were strongly related to different patients' characteristics. In multivariate analysis, the most important predictors of both OS and AML transformation risk were number of chromosomal abnormalities (P

Trisomy 11 in myelodysplastic syndromes (MDS) is rare, with undefined clinical significance and is currently assigned to the International Prognostic Scoring System (IPSS) intermediate-risk group. Over a 15-year period, we identified 17 MDS patients with trisomy 11 either as a sole abnormality (n=10) or associated with one or two additional alterations (n=7), comprising 0.3% of all MDS cases reviewed. Of 16 patients with Bone Marrow material available for review, 14 (88%) patients presented with excess blasts, 69% patients evolved to acute myeloid leukemia (AML) in a 5-month median interval and the median survival was 14 months. For comparison, we studied 19 AML patients with trisomy 11 in a noncomplex karyotype, of which, a substantial subset of patients had morphologic dysplasia, and/or preexisting cytopenia(s)/MDS. Genomic DNA PCR showed MLL partial tandem duplication in 5 of 10 MDS and 7 of 11 AML patients. A review of literature identified 17 additional cases of MDS with trisomy 11, showing similar clinicopathologic features to our patients. Compared with our historical data comprising 1165 MDS patients, MDS patients with trisomy 11 had a significantly inferior survival to patients in the IPSS intermediate-risk cytogenetic group (P=0.0002), but comparable to the poor-risk group (P=0.97). We conclude that trisomy 11 in MDS correlates with clinical aggressiveness, may suggest an early/evolving AML with myelodysplasia-related changes and is best considered a high-risk cytogenetic abnormality in MDS prognostication.

Acute erythroleukemia (AML-M6) is an uncommon subtype of acute myeloid leukemia (AML); it is considered to have a poor prognosis. From 1 January 1980 to 21 May 2008, 91 patients with newly diagnosed AML-M6 were seen at the University of Texas–M.D. Anderson Cancer Center (UT–MDACC). Forty-five patients (50%) had a history of myelodysplatic syndrome (MDS), compared with 41% in our control group (patients with other AML subtypes) (P=0.08). Poor-risk cytogenetics were more common in patients with AML-M6 (61% versus 38%, P=0.001). Complete remission rates were 62% for patients with AML-M6, comparing with 58% for the control group (P=0.35). Median disease free survival (DFS) for patients with AML-M6 was 32 weeks, versus 49 weeks for the control group (P=0.05). Median overall survival (OS) of patients with AML-M6 was 36 weeks, compared with 43 weeks for the control group (P=0.60). On multivariate analysis for DFS and OS, AML-M6 was not an independent risk factor. AML-M6 is commonly associated with a previous diagnosis of MDS and poor-risk karyotype. The diagnosis of AML-M6 does not impart by itself a worse prognosis, and treatment decisions on this disease should be guided by well known AML prognostic factors.

Hck and Lyn are required in Philadelphia chromosome (Ph) positive acute lymphocytic leukemia (ALL). Here, we present evidence that the promoter CpG island of Hck, but not of Lyn, is aberrantly methylated in leukemia. Hck promoter DNA methylation was detected in 13 out of 23 (56.5%) hematopoietic and eight out of 10 (80%) non-hematopoietic cell lines, but not in normal controls. Treatment with 5-aza-2'-deoxycytidine induced demethylation and restoration of Hck mRNA and protein expression. Hck methylation (> or =15%) was detected in nine out of 44 (20%) patients with Ph negative ALL, and in one out 16 (6%) patients with Ph positive ALL, but not in patients with AML or chronic myelogenous leukemia. In this subset of patients, low levels of Hck methylation (10-15%) were observed in 26-30% of patients. Lyn methylation was observed in three out of 28 (10.7%) cell lines, but only in one out of 71 (1.4%) patients. Patients with Ph negative ALL and Hck methylation had a poorer prognosis. These data indicate that Hck may have tumor suppressor properties in BCR-ABL negative leukemia.

Acute myeloid leukemia (AML) is the second most common form of leukemia and the most frequent cause of leukemia-related deaths in the United States. The incidence of AML increases with advancing age and the prognosis for patients with AML worsens substantially with increasing age. Many older patients are ineligible for intensive treatment and require other therapeutic approaches to optimize clinical outcome. To address this treatment gap, novel agents with varying mechanisms of action targeting different cellular processes are currently in development. Hypomethylating agents (azacitidine, decitabine, SGI-110), histone deacetylase inhibitors (vorinostat, pracinostat, panobinostat), FMS-like tyrosine kinase receptor-3 inhibitors (quizartinib, sorafenib, midostaurin, crenolanib), cytotoxic agents (clofarabine, sapacitabine, vosaroxin), cell cycle inhibitors (barasertib, volasertib, rigosertib) and monoclonal antibodies (gentuzumab ozogamicin, lintuzumab-Ac225) represent some of these promising new treatments. This review provides an overview of novel agents that have either completed or are currently in ongoing phase III trials in patients with previously untreated AML for whom intensive treatment is not an option. Other potential drugs in earlier stages of development will also be addressed in this review.

The clinical features and outcomes of 148 patients with acute myeloid leukemia (AML) and 11q23 chromosomal abnormalities were compared with those of 2640 patients with non-11q23 AML. Patients with t(9;11)), t(6;11), or other 11q23 balanced translocations [t(11;v)(q23;v)] presented at a younger age and with higher percentage of bone marrow blasts. Unbalanced 11q23 abnormalities were commonly associated with deletions of chromosomes 5q, 7q and/or complex karyotypes. In multivariate analysis, when compared to patients with non-11q23 AML and unfavorable risk karyotype, there was a significant difference in overall survival (OS) for patients with t(9;11) (P = .004), whereas there were no difference in OS for patients with t(6;11) (P = .62), t(11;19) (P = 0.20), and unbalanced 11q23 aberrations (P = .85) or t(11;v)(q23;v) (P = 0.59), indicating that t(9;11) has an independent intermediate prognostic factor, with all others poor prognostic factors for OS; this was further confirmed by comparing them with patients with non-11q23 AML and intermediate risk karyotype. Using intention-to treat analysis based on donor availability, we also noted that allogeneic stem cell transplant (SCT) in first remission had a significant benefit towards improving OS (P < 0.001) and relapse-free survival (P

Amplification of the NUP214-ABL1 oncogene can be detected in patients with T cell acute lymphoblastic leukemia (T-ALL). We screened 29 patients with T cell malignancies for the expression of NUP214-ABL1 by reverse transcription-polymerase chain reaction (RT-PCR). NUP214-ABL1 was detected in three (10%) patients. These results were confirmed by fluorescence in situ hybridization techniques. We also studied the activity of imatinib, nilotinib and dasatinib against the human NUP214-ABL1-positive cell lines PEER and BE-13. All three tyrosine kinase inhibitors decreased the viability of PEER and BE-13 cells, but nilotinib and dasatinib had >1-log lower IC(50) values than imatinib (P

MicroRNAs (miRNAs) are a family of 19-24 nucleotide noncoding RNAs (ncRNAs) with posttranscriptional regulatory functions. Increasing evidences from the literature show that miRNAs play a pivotal role in human tumorigenesis. Many studies have addressed the role of miRNAs in normal hematopoiesis, giving an interpretative key to the aberrancies of expression observed in human hematological malignancies. Moreover, the recent demonstration that other ncRNAs, the ultraconserved genes (UCGs) or transcribed ultraconserved regions (T-UCRs), are involved in human cancerogenesis, suggests that the wider family of ncRNAs (including both miRNAs and UCGs) could contribute to the development of the malignant phenotype. Here we review the main studies investigating the role of miRNAs and UCRs in both normal hemopoiesis and hematological malignancies, and identify the molecular, clinical and therapeutic implications of these recent findings.

Current prognostic models for myelodysplastic syndromes (MDS) do not allow the identification of patients with lower risk disease and poor prognosis that may benefit from early therapeutic intervention. We evaluated the characteristics of 856 patients with low or intermediate-1 disease by the International Prognostic Scoring System. Mean follow-up was 19.6 months (range 1-262). Of these patients, 87 (10%) transformed to acute myelogenous leukemia, and 429 (50%) had died. By multivariate analysis, characteristics associated with worse survival (P

In reply to ‘Improving the prognostic evaluation of patients with lower-risk myelodysplastic syndromes’ by Kuendgen et al.