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Acute myeloid leukemia (AML) is a malignancy characterized by differentiation arrest of hematopoietic precursor cells. Differentiation therapy is effective for patients with acute promyelocytic leukemia; however, only a few effective differentiation therapies have been established for patients with other AML subtypes. In this study, seven benzimidazole anthelmintics were examined to determine the effects of differentiation on AML cells. The expression of monocyte markers (CD11b and CD14) was elevated after treatment with most benzimidazole anthelmintics. Among these drugs, parbendazole (PBZ) induced AML cell differentiation at low concentration. PBZ induced the monocyte marker expression, KLF4/DPYSL2A gene expression, and apoptosis for 21 AML cell lines with various subtypes and a primary AML sample. Finally, an in vivo analysis using an AML patient-derived xenograft mouse model showed a significant decrease in the chimerism level and prolonged survival in PBZ-treated mice. These findings could lead to a more effective differentiation therapy for AML. Low concentrations of the anthelmintic parbendazole (PBZ) induces monocytic differentiation in AML cells and PBZ could be a candidate for drug repositioning. [ABSTRACT FROM AUTHOR]

Summary: Differentiation therapy is a less toxic but still a very effective treatment for a subset of acute myeloid leukaemia (AML) cases. With the goal to identify novel compounds that can effectively and safely induce the terminal differentiation of non‐acute promyelocytic leukaemia (APL) AML cells, we performed a chemical screening and identified albendazole (ABZ), a widely used anti‐helminthic drug, as a promising lead compound that can differentiate non‐APL AML cells by stimulating the Krüppel‐like factor 4‐dihydropyrimidinase‐like 2A (KLF4‐DPYSL2A) differentiation axis to the monocytes. Our in vitro and in vivo findings demonstrate that ABZ is an attractive candidate drug as a novel differentiation chemotherapy for patients with non‐APL AML. [ABSTRACT FROM AUTHOR]

Summary: KIT D816V mutation within exon 17 has been particularly reported as one of the poor prognostic factors in pediatric acute myeloid leukemia (AML) with RUNX1‐RUNX1T1. The exact frequency and the prognostic impact of KIT D816V minor clones at diagnosis were not examined. In this study, the minor clones were examined and the prognostic significance of KIT D816V mutation in pediatric patients was investigated. Consequently, 24 KIT D816V mutations (7.2%) in 335 pediatric patients were identified, and 12 of 24 were only detected via the digital droplet polymerase chain reaction method. All 12 patients were confined in core binding factor (CBF)‐AML patients. The 5 year event‐free survival of the patients with KIT D816V mutation was significantly inferior to those without KIT D816V mutation (44.1% [95% confidence interval (CI), 16.0%–69.4%] vs. 74.7% [95% CI, 63.0%–83.2%] P‐value = 0.02, respectively). The 5 year overall survival was not different between the two groups (92.9% [95% CI, 59.0%–NA vs. 89.7% [95% CI, 69.6%–96.8%] P‐value = 0.607, respectively). In this study, KIT D816V minor clones in patients with CBF‐AML were confirmed and KIT D816V was considered as a risk factor for relapse in patients with RUNX1‐RUNX1T1‐positive AML. [ABSTRACT FROM AUTHOR]

Keywords: acute megakaryoblastic leukemia; Down syndrome; CLEC12A; TIM3; CD96 EN acute megakaryoblastic leukemia Down syndrome CLEC12A TIM3 CD96 e7 e11 5 12/21/20 20210101 NES 210101 Acute myeloid leukaemia (AML) is a genetically and clinically heterogeneous disease, characterized by expansion of undifferentiated myeloid precursor cells.1 Despite an increased understanding of the biology and therapeutic advances, the outcomes of AML patients remain unsatisfactory. The average CLEC12A-positive cell rate was significantly lower in FAB-M7 cases (10-8%) than that in non-FAB-M7 cases (91-8%, I P i = 2.8E-20; Fig 1C); however, the average TIM3-positive cell rate did not differ significantly between the two groups (67-5% vs. 62-1%, respectively, I P i = 0-66). The average CD96-positive cell rate was also significantly lower in samples from FAB-M7 patients (20-7%) than in those from non-FAB-M7 patients (59-5%, I P i = 0-0002). [Extracted from the article]

Although the biological importance of Krüppel-like factor 4 (KLF4) transcription factor in the terminal differentiation of hematopoietic cells to the monocytes has been well established, the underlying mechanisms remain elusive. To clarify the molecular basis of KLF4-mediated monocytic differentiation, we performed detailed genetic studies in acute myeloid leukemia (AML) cells. Here, we report that dihydropyrimidinase like 2 (DPYSL2), also known as CRMP2, is a novel key differentiation mediator downstream of KLF4 in AML cells. Interestingly, we discovered that KLF4-mediated monocytic differentiation is selectively dependent on one specific isoform, DPYSL2A, but not on other DPYSL family genes. Terminal differentiation to the monocytes and proliferation arrest in AML cells induced by genetic or pharmacological upregulation of KLF4 were significantly reversed by short hairpin RNA (shRNA)-mediated selective depletion of DPYSL2A. Chromatin immunoprecipitation assay revealed that KLF4 associates with the proximal gene promoter of DPYSL2A and directly transactivates its expression. Together with the unique expression patterns of KLF4 and DPYSL2 limited to the differentiated monocytes in the hematopoietic system both in human and mouse, the identified KLF4-DPYSL2 axis in leukemia cells may serve as a potential therapeutic target for the development of novel differentiation therapies for patients with AML. [ABSTRACT FROM AUTHOR]

Thioredoxin‐interacting protein (TXNIP) has been widely recognized as a tumor suppressor in various cancers, including liver, breast, and thyroid cancers. Although TXNIP is epigenetically silenced in acute myeloid leukemia (AML) cells, as in many cancer cells, its role in leukemogenesis remains elusive. Mixed‐lineage leukemia (MLL) gene rearrangements in AML are associated with poor prognosis, and the development of a new treatment method is eagerly anticipated. In this study, we first reveal that lower expression of TXNIP is correlated with shortened overall survival periods in AML patients. Moreover, we demonstrated that TXNIP overexpression significantly suppresses proliferation in AML cells harboring MLL fusion genes. TXNIP promotes autophagy by increasing expression of the autophagy protein, Beclin 1, and lipidation of LC3B. We also show that TXNIP overexpression combined with ABT263, a potent inhibitor of Bcl‐2 and Bcl‐xL, is highly effective at inducing cell death in MLL‐rearranged (MLL‐r) AML cells. In summary, this study provides insights into the molecular mechanism of TXNIP‐mediated tumor suppression and furthermore underscores the potential of TXNIP as a promising therapeutic target for MLL‐r AML. [ABSTRACT FROM AUTHOR]

Abstract: Background: Gene abnormalities, particularly chromosome rearrangements generating gene fusion, are associated with clinical characteristics and prognosis in pediatric acute myeloid leukemia (AML). Karyotyping is generally performed to enable risk stratification, but the results are not always consistent with those of reverse transcription–polymerase chain reaction (RT‐PCR), and more accurate and rapid methods are required. Methods: A total of 487 samples from de novo AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML‐05 study (n = 448), and from acute promyelocytic leukemia (APL) patients enrolled in the JPLSG AML‐P05 study (n = 39) were available for this investigation. Multiplex quantitative RT‐PCR was performed to detect eight important fusion genes: AML1(RUNX1)‐ETO(RUNX1T1), CBFB‐MYH11, MLL(KMT2A)‐AF9(MLLT3), MLL‐ELL, MLL‐AF6(MLLT4), FUS(TLS)‐ERG, NUP98‐HOXA9, and PML‐RARA. Results: Fusion genes were detected in 207 (46.2%) of the 448 AML‐05 patient samples. After exclusion of two samples with PML‐RARA, no chromosomal abnormalities were identified on karyotyping in 19 of 205 patients (9.3%) positive for fusion genes on RT‐PCR. Fusion genes were confirmed on fluorescence in situ hybridization (FISH) in 11 of these 19 patients. In contrast, fusion genes were detected in 37 of 39 patients (94.9%) from the AML‐P05 study, and 33 of these results were consistent with the karyotyping. There were discrepancies in four patients (10.8%), three with normal karyotypes and one in whom karyotyping was not possible. All four of these patients were PML‐RARA positive on FISH. Conclusions: Multiplex quantitative RT‐PCR‐based fusion gene screening may be effective for diagnosis of pediatric AML. [ABSTRACT FROM AUTHOR]

Abstract: Background: In acute myeloid leukemia (AML), accurate detection of minimal residual disease (MRD) enables better risk‐stratified therapy. There are few studies, however, on the monitoring of multiple fusion transcripts and evaluation of their accuracy as indicators of MRD at multiple time points. Methods: We retrospectively examined RNA obtained from 82 pediatric AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML‐05 study. The expression of six important fusion transcripts (AML1(RUNX1)‐ETO, CBFB‐MYH11, MLL(KMT2A)‐AF9, MLL‐ELL, MLL‐AF6, and FUS‐ERG) was analyzed at five time points 30–40 days apart following diagnosis. Results: In patients with AML1‐ETO (n = 36 at time point 5), all six patients with >3,000 copies and four of 30 patients with ≤3,000 copies relapsed. AML1‐ETO transcripts persisted during treatment even in patients without relapse, as well as CBFB‐MYH11 transcripts. In contrast, in patients with MLL‐AF9 (n = 9 at time point 5), two patients were positive for MLL‐AF9 expression (>50 copies) and both relapsed. Only one of seven MLL‐AF9‐negative patients relapsed. In the AML1‐ETO group, MRD‐positive patients (>3,000 copies at time point 5) had significantly lower relapse‐free survival (RFS; P < 0.0001) and overall survival (OS; P = 0.009) than MRD‐negative patients. Similarly, in the MLL‐AF9 group, MRD‐positive patients (>50 copies at time point 5) had significantly lower RFS (P = 0.002) and OS (P = 0.002) than MRD‐negative patients. Conclusions: Detection of MLL‐AF9 transcripts on real‐time quantitative polymerase chain reaction is a promising marker of relapse in pediatric AML. In contrast, the clinical utility of detecting AML1‐ETO and CBFB‐MYH11 expression is limited, although higher AML1‐ETO expression can be a potential predictor of relapse when assessed according to an optimal threshold. [ABSTRACT FROM AUTHOR]

Background The combination of fludarabine (Flu), high-dose cytarabine (Ara-C) and granulocyte colony-stimulating factor (G- CSF; FLAG), with anthracyclines has become standard chemotherapy for refractory acute myeloid leukemia ( AML) in European children and adults. To clarify the efficacy and the safety of FLAG-idarubicin ( IDA) for children prospectively, we planned a multicenter phase II study ( AML-R11) by the Japanese Pediatric Leukemia/Lymphoma Study Group. Methods Patients with AML aged between 2 and 20 years old, who had the first bone marrow ( BM) relapse or induction failure, were enrolled. The FLAG- IDA regimen consisted of Flu 30 mg/m2 for 5 days, Ara-C 2 g/m2 for 5 days, G- CSF (lenograstim) 5 μg/kg for 6 days and IDA 10 mg/m2 for 3 days. The primary endpoint was remission rate after therapy. Results Due to drug supply issues, the trial was suspended after the inclusion of seven eligible patients. There were six cases of early relapse within 1 year of the first remission. All seven patients completed the therapy and no early death was observed. Hematological toxicity was common, and one patient developed grade 4 non-hematological toxicity of bacterial meningitis. Although only one patient with late relapse achieved complete remission, minimal residual disease was positive on both flow cytometry and Wilms' tumor 1 mRNA. Two patients were alive in remission following hematopoietic stem cell transplantation, whereas the other five patients died of either the disease or treatment-related causes. Conclusion FLAG- IDA might be tolerable for children with refractory AML although the efficacy should be further investigated. [ABSTRACT FROM AUTHOR]