Search

Abstract Background Blast transformation is a rare but well-recognized event in Philadelphia-negative myeloproliferative neoplasms associated with a poor prognosis. Secondary acute myeloid leukemias evolving from myeloproliferative neoplasms are characterized by a unique set of cytogenetic and molecular features distinct from de novo disease. t(8;21) (q22;q22.1); RUNX1::RUNX1T1, one of the most frequent cytogenetic abnormalities in de novo acute myeloid leukemia, is rarely observed in post-myeloproliferative neoplasm acute myeloid leukemia. Here we report a case of secondary acute myeloid leukemia with t(8;21) evolving from JAK2-mutated essential thrombocythemia. Case presentation The patient was a 74-year-old Japanese woman who was referred because of thrombocytosis (platelets 1046 × 109/L). Bone marrow was hypercellular with increase of megakaryocytes. Chromosomal analysis presented normal karyotype and genetic test revealed JAK2 V617F mutation. She was diagnosed with essential thrombocythemia. Thrombocytosis had been well controlled by oral administration of hydroxyurea; 2 years after the initial diagnosis with ET, she presented with leukocytosis (white blood cells 14.0 × 109/L with 82% of blasts), anemia (hemoglobin 91 g/L), and thrombocytopenia (platelets 24 × 109/L). Bone marrow was hypercellular and filled with 80% of myeloperoxidase-positive blasts bearing Auer rods. Chromosomal analysis revealed t(8;21) (q22;q22.1) and flow cytometry presented positivity of CD 13, 19, 34, and 56. Molecular analysis showed the coexistence of RUNX1::RUNX1T1 chimeric transcript and heterozygous JAK2 V617F mutation in leukemic blasts. She was diagnosed with secondary acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 evolving from essential thrombocythemia. She was treated with combination chemotherapy with venetoclax and azacytidine. After the first cycle of the therapy, blasts disappeared from peripheral blood and decreased to 1.4% in bone marrow. After the chemotherapy, RUNX1::RUNX1T1 chimeric transcript disappeared, whereas mutation of JAK2 V617F was still present in peripheral leukocytes. Conclusions To our best knowledge, the present case is the first one with JAK2 mutation preceding the acquisition of t(8;21). Our result suggests that t(8;21); RUNX1::RUNX1T1 can be generated as a late event in the progression of JAK2-mutated myeloproliferative neoplasms. The case presented typical morphological and immunophenotypic features associated with t(8;21) acute myeloid leukemia.

Background: AIDS-related NK/T-cell lymphoma is a rare subtype of AIDS-related lymphomas, characterized by a poor prognosis and lack of standardized treatment protocols. To date, there have been no reported cases of AIDS-associated NK/T-cell lymphoma in remission followed by treatment-related acute myeloid leukemia (t-AML), where both the lymphoma and AML achieved remission and long-term survival through chemotherapy alone. Case presentation: We report a case of a patient diagnosed with AIDS-related extra-nodal NK/T-cell lymphoma (ENKTCL). The patient achieved complete remission after receiving six cycles of chemotherapy, local radiotherapy, and combination antiretroviral therapy (cART). Throughout the follow-up period, the patient continued cART treatment, maintaining an HIV-RNA level below the lower limit of detection. However, 70 months later, the patient developed new symptoms and was subsequently diagnosed with acute myeloid leukemia (AML) M4 subtype. Following the completion of 10 cycles of chemotherapy and ongoing cART, the patient achieved complete remission of AML, with an overall survival time exceeding 103 months from the initial ENKTCL diagnosis. Conclusions: This case highlights the effectiveness of chemotherapy combined with cART in the treatment of AIDS-associated NK/T-cell lymphoma and secondary treatment-related leukemia. This approach may serve as a viable option for patients who are not candidates for bone marrow transplantation. Furthermore, this case underscores the importance of long-term follow-up in the management of AIDS-associated malignancies.

Objective To explore the effect of vemurafenib (VEM) combined with chidamide (CDM) on cellular senescence in secondary acute myeloid leukemia (sAML). Methods sAML cell lines SKM-1 and MOLM-13 were divided into control group (sAML cells), VEM group (sAML cells treated with VEM), CDM group (sAML cells treated with CDM), and COM group (sAML cells treated with VEM combined with CDM)(n=3). CCK-8 assay was used to measure the viability of sAML cells. Immunofluorescence assay was used to verified the cellular senescence of sAML cells. Flow cytometry was used to detect cell cycle and apoptosis of sAML cells. Network pharmacology and RT-qPCR were used to analyze and verify the mechanism of VEM combined with CDM. Results VEM inhibited the proliferation of sAML cells lines in a time- and dose-dependent manner(P < 0.05), the half-maximal inhibitory concentration (IC50) of VEM on SKM-1 and MOLM-13 cells was 24.15±1.18 and 11.30±0.38 μmol/L(P < 0.0001), respectively. VEM (SKM-1: 1/3 IC50-VEM, MOLM-13: 1/2 IC50-VEM) combined with CDM synergistically promoted sAML cellular senescence by upregulating TRF2 and Lamin B1, characterized cycle stagnation in G0/G1 phase(P < 0.05), inhibiting cell proliferation(P < 0.01) and promoting cell apoptosis (P < 0.05). Swiss Target Predict, TargetNe, SEA and PharmMapper discovered the core targets and signaling pathways of VEM collaborating with CDM. RT-qPCR verified that VEM collaborated with CDM to promote senescence of sAML cells through inhibiting PI3K-AKT and MAPK signaling pathways(P < 0.05). Conclusion VEM combined with CDM can induce cellular senescence of sAML cells by downregulating PI3K-AKT and MAPK signaling pathways, inhibiting proliferation and promoting apoptosis of sAML cells. VEM combined with CDM might be a new regime for patients with sAML.

Abstract We compared outcomes of adult patients with secondary acute myeloid leukemia (sAML) versus de novo AML after non-T-depleted haploidentical stem cell transplant (HaploSCT) with post-transplant cyclophosphamide (PTCy). Seventeen hundred and eleven AML patients (sAML-231, de novo-1480) in first complete remission transplanted from 2010 to 2021, were included. Patients with de novo AML were younger, median age 55.8 versus 60.8 years, p

Objective: Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder with a high propensity to develop into acute myeloid leukemia (AML). Although abnormal microRNA expression has been implicated in MDS, the exact role of miR-181a-2-3p has not been entirely elucidated. Here, we investigated miR-181a-2-3p levels in bone marrow (BM), and described its utility as a potential indicator for MDS diagnosis and prognosis.Methods: We evaluated miR-181a-2-3p expression in BM samples of 54 newly diagnosed MDS cases, 16 sAML patients and 32 healthy donors and then assessed its association with clinical characteristics and its potential value for MDS diagnosis and prognosis.Results: Compared with healthy controls, miR-181a-2-3p levels were decreased in the total cohort of MDS patients. Additionally, in MDS patients with secondary AML (sAML), miR-181a-2-3p was over-expressed relative to levels in those without this form. The areas under the curve of receiver operating characteristic curves were 0.700 and 0.750 to distinguish MDS patients from controls and sAML from newly diagnosed MDS, respectively. Kaplan–Meier analysis showed a positive correlation between miR-181a-2-3p expression and overall survival (OS). Further, multivariate analysis indicated that miR-181a-2-3p was an independent prognostic index for MDS with respect to OS.Conclusion: Decreased miR-181a-2-3p expression in MDS patients may be considered as one of the underlying markers reflecting MDS progression and prognosis.

Objective To investigate the effects of combined application of chidamide (CDM) and mycophenolate mofetil (MMF) on the proliferation of secondary acute myeloid leukemia (sAML) cells. Methods Chronic myeloid leukemia blast-phase cell line K562 and myelodysplastic syndromes (MDS)-transformed leukocyte line SKM-1 were employed in the study. The cells were divided into groups according to different concentrations of intervention drugs: CDM alone groups (0.25, 0.5, 1, 2 and 4 μmol/L), MMF alone groups (0.5, 1, 2, 4 and 8 μmol/L) and combined drug groups (CDM∶MMF=1∶2), respectively. The inhibitory rate of cell proliferation was detected by CCK-8 assay after treatment for 24, 48 and 72 h, respectively. Moreover, the changes of cell cycle and apoptotic rate were determined by flow cytometry after 72 h of intervention under the optimal combined drug concentration, and its mechanism was analyzed by network pharmacology. Results CCK-8 assay showed that the combination index of the combined drug group (1 μmol/L CDM+2 μmol/L MMF) was 0.389 44 in K562 cells and 0.630 98 in SKM-1 cells. When compared with the CDM and MMF monotherapy groups, the combined treatment significantly enhanced the inhibitory effect on the proliferation of both K562 and SKM-1 cells (P < 0.01), and increased the apoptotic rate of K562 cells (P < 0.05). As compared with the MMF alone group, the combination group remarkably arrested the cell cycle at the G0/G1 phase, though which had no statistical difference with CDM alone. Subsequently, a drug-disease target protein-protein interaction (PPI) network including 66 nodes and 222 edges was constructed through network pharmacology, and 9 core targets including CDK1, CDK2, CDK4, CDK6, CDK9, SYK, BTK, KDR, and PIK3CB were screened out according to topology. Enrichment analysis indicated that various biological processes such as protein phosphorylation, cell proliferation, and apoptosis regulation were mainly involved, as well as PI3K-AKT, FOXO and other signaling pathways. Conclusion CDM combined with MMF significantly inhibits the growth of sAML cells.

Background Secondary acute myeloid leukemia (S-AML) patients generally have a poor prognosis, but the chromosomal aberrations of S-AML have been rarely reported. We aimed to explore the chromosomal aberrations and clinical significance in patients with S-AML. Patients and methods The clinical characteristics and karyotypes of 26 patients with S-AML were retrospectively analyzed. The overall survival (OS) was measured from the time of the patients’ transition to AML (i.e., at S-AML diagnosis). Results The study included 26 S-AML patients (13 males and 13 females), with a median age of 63 years (range, 20–77 years). They transformed from various hematologic malignancies or solid tumors; most of them were secondary to myelodysplastic syndrome (MDS). About 62% of the S-AML patients showed chromosomal aberrations. The serum lactate dehydrogenase (LDH) level in S-AML patients with abnormal karyotype was higher than those with normal karyotype. Apart from the differences in treatment regimens, S-AML patients with chromosomal aberrations had shorter OS (P

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by the presence of cytopenias, ineffective hematopoiesis and frequent transformation into secondary acute myeloid leukemia (secAML). Recent genomic studies provide unprecedented insight into the molecular landscape of clonal proliferation in MDS. Genetic diversity of both MDS and secAML subclones cannot be defined by a single somatic mutation. Mutations of the founding clone may survive over implemented chemotherapy and allogenic hematopoietic cell transplantation (alloHCT), but new subclonal mutations may also appear. Next generation sequencing (NGS) makes it possible to define the mutational profile of disease subclones during the treatment course and has a potential in pre- and post-alloHCT monitoring. Understanding the molecular pathophysiology of MDS may soon allow for monitoring the course of disease and personalized treatment depending on the mutational landscape. In the present paper we report, for the first time in MDS, ASXL1 c.1945G>T, TET2 c.4044+2dupT and c.4076G>T sequence variants. Moreover, we detected RUNX1 c.509-2A>C and SF3B1 c.1874G>T sequence variants. Furthermore, we verify the clinical utility of NGS and pyrosequencing in MDS and secAML.

Background. Secondary malignancies in pediatric cancer survivors is an actual problem in modern oncopediatry. Alkylating agents and topoisomerase II inhibitors used for primary tumors treatment, induce secondary acute myeloid leukemia (sAML), which treatment results are unsatisfactory.Objective. By predicating on literature and own data to evaluate clinical and biologic features and therapeutic potential of pediatric sAML.Materials and methods. Six patients (age 7–16 years) with sAML were enrolled the study from June 1998 to December 2016. Follow up until September 2020. Primary tumors, which therapy could induce sAML were acute lymphoblastic leukemia, Burkitt lymphoma, germ cell tumor, osteosarcoma, nephroblastoma.Results and conclusion. From 6 patients, included in the study, 2 are alive (+58 and +67 months after allogenic stem cell transplantation), that match global data. Fludarabine-containing regimens and allogeneic hematopoietic stem cell transplant could be a method of choice for this unfavorable group of patients.

Despite continuous attempts to improve therapy, the outcomes of acute myeloid leukemia remain almost unchanged over last decades. Drugs made with a more complete understanding of the biology of acute myeloid leukemia do not equal the hopes for better prognosis. The best results are achieved only with high-dose chemotherapy, which is only possible for a limited number of patients. High phenotypic and genotypic heterogeneity of acute myeloid leukemia defines the relevance to develop personalized approaches to therapy, including those based on determination of individual drug sensitivity of blast cells.This article presents the results of developing an ex-vivo model of acute myeloid leukemia, as well as testing of two in vitro sensitivity assessment methods: evaluation of the genotoxicity of drugs in the micronucleus test and vitality and sensitivity to chemotherapy in sorted blast cells. Prospects of individualized therapy of acute myeloid leukemia were determined based on introduction into clinical practice and continuing the research.

Secondary acute myeloid leukemia (sAML) is a high-risk AML evolving from heterogenous prior hematological disorders. Compared to de novo AML, sAML has even worse responses to current therapy and thus is associated with lower remission rates, inferior overall survival (OS) and higher relapse rates. Many efforts have been devoted to improving the overall but with limited success, and novel strategy is thus highly needed. Recent research has identified that CLL1 is highly expressed on AML leukemia stem cells and blasts cells but not on normal hematopoietic stem cells. In this case report, we treated a secondary AML patient with anti -CLL1 CAR-T therapy and achieved morphological, immunophenotypic and molecular complete remission for over 10 months. Although only one successful case is presented here, the anti-CLL1 CAR T-cells should be considered as another treatment option for secondary AML in the future.

The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47), and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu). All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation). Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift) and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q) potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation.