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Acute myeloid leukemia (AML) is one of the most aggressive hematopoietic malignancies. Patients still suffer from refractory/relapsed disease after anthracycline-based therapy, which leads to a poor prognosis. N6-Methyladenosine (m6A) is the most abundant post-transcriptional modification in eukaryotes, the imbalance of which is reported to be associated with various pathological processes, including drug resistance. However, the relationship between m6A modification and drug resistance has not been well defined in AML. In this study, we analyzed the sequencing data of HL60 and its Adriamycin-resistant cell line HL60/ADR. We found a total of 40,550 m6A-methylated peaks, representing 15,640 genes in HL60, and 38,834 m6A-methylated peaks, representing 15,285 genes in HL60/ADR. KEGG pathway analysis showed that pathways were enriched in the FoxO signaling pathway, p53 signaling pathway, and Notch signaling pathway. MeRIP-seq results showed that the fold enrichment of the global m6A level in HL60/ADR was higher than that in HL60, and dot blot assay results indicated that the global m6A level was elevated in HL60/ADR cells compared with that in HL60 cells. Further analysis revealed that the expression level of METTL3 was elevated in HL60/ADR cells compared with that in HL60 cells. After a combined treatment of STM2457 (an inhibitor of METTL3) and Adriamycin, the proliferation of HL60/ADR was inhibited. Thus, we hypothesized that the abnormality of m6A modification played an important role in Adriamycin-resistant AML. [ABSTRACT FROM AUTHOR]

Chidamide, a novel histone deacetylase inhibitor, has exerted effects in T-cell tumors through various mechanisms. Seventeen patients with refractory or relapsed T-cell acute lymphoblastic lymphoma/leukemia (T-LBL/ALL) received Chidamide combined with chemotherapy as salvage treatment. Historical data was analyzed as comparison as chemotherapy group. Complete response (CR) rate and overall response rate (ORR) of Chidamide + chemotherapy group were higher than that of chemotherapy group after one course. Chidamide + chemotherapy group had a better progress-free survival (PFS) compared to chemotherapy group. No difference in overall survival (OS) was observed. Grade 3/4 nonhematological adverse events (>10%) of patients in Chidamide + chemotherapy group included febrile neutropenia (64.7%), drug-induced liver failure (17.6%), decreased fibrinogen (11.8%), sepsis (11.8%), pneumonitis (11.8%), and oral mucositis (11.8%). This study demonstrates that Chidamide included regimen may be a new treatment strategy with an acceptable safety profile for refractory or relapsed T-LBL/ALL patients but requires further investigation. [ABSTRACT FROM AUTHOR]

The comparative efficacy and safety of antithymocyte globulin (ATG) at fixed doses in patients undergoing allogeneic peripheral blood stem cell transplantation from unrelated donors (UR-PBSCT) has not been evaluated. In this study, the records of 56 patients and 54 patients who received pre-transplant ATG-Thymoglobulin (ATG-T) at a total dose of 10 mg/kg and ATG- Fresenius (ATG-F) at a total dose of 20 mg/kg, respectively, were retrospectively analyzed. ATG-F patients had a significantly lower probability of developing chronic graft-vs-host disease (cGVHD) than those treated with ATG-T (p= 0.04). ATG-F was associated with a non-significant trend towards lower relapse rates and higher survival at 3- and 5-years of follow-up compared with ATG-T. A significantly greater proportion of ATG-T patients experienced chills and high fever than ATG-F patients (p< 0.01). The current findings suggest that ATG-F may more effectively and safely prevent cGVHD without increasing relapse rates in patients undergoing UR-PBSCT. [ABSTRACT FROM PUBLISHER]

A nonlinear recurrence involving a piecewise constant McCulloch-Pitts function and 2k-periodic coefficient sequences is investigated. By allowing the threshold parameter to vary from 0 to ∞, we work out a complete bifurcation analysis for the asymptotic behaviors of the corresponding solutions. Among other things, we show that each solution tends towards one of four different limits. Furthermore, the accompanying initial regions for each type of solutions can be determined. It is hoped that our analysis will provide motivation for further results for recurrent McCulloch-Pitts type neural networks. [ABSTRACT FROM AUTHOR]

The mixed-lineage leukemia (MLL)-AF4 fusion protein encoded by the chromosomal translocation t(4;11) predicts a poorer prognosis in acute lymphoblastic leukemia (ALL) than in other MLL-associated leukemias. However, the detailed mechanism underlying regulation of MLL-AF4 expression remains largely unknown. In this study, we showed that microRNA (miR)-142-3p was significantly downregulated in ALL patients expressing MLL-AF4. Upregulation of miR-142-3p decreased MLL-AF4 expression in the RS4;11 leukemic cell line, which suggests that MLL-AF4 is a direct target of miR-142-3p. Ectopic expression of miR-142-3p remarkably suppressed cell proliferation and induced apoptosis in RS4;11 cells expressing the MLL-AF4 fusion protein. We also found that exogenous expression of miR-142-3p strongly reduced the expression of MLL-AF4 target genes such as homeobox A (HOXA)9, HOXA7, and HOXA10 in RS4;11 cells. Taken together, our results indicate that miR-142-3p functions as a growth suppressor in MLL-AF4 + ALL, and its suppressive effects are mediated primarily through repression of MLL-AF4 expression. [ABSTRACT FROM AUTHOR]

The chromatins are folded into three-dimensional (3D) structures inside cells, which coordinates the regulation of gene transcription by the non-coding regulatory elements. Aberrant chromatin 3D folding has been shown in many diseases, such as acute myeloid leukemia (AML), and may contribute to tumorigenesis. The anthracycline topoisomerase II inhibitors can induce histone eviction and DNA damage. We performed genome-wide high-resolution mapping of the chemotherapeutic effects of various clinically used anthracycline drugs. ATAC-seq was used to profile the histone eviction effects of different anthracyclines. TOP2A ChIP-seq was used to profile the potential DNA damage regions. Integrated analyses show that different anthracyclines have distinct target selectivity on epigenomic regions, based on their respective ATAC-seq and ChIP-seq profiles. We identified the underlying molecular mechanism that unique anthracycline variants selectively target chromatin looping anchors via disrupting CTCF binding, suggesting an additional potential therapeutic effect on the 3D genome. We further performed Hi-C experiments, and data from K562 cells treated with the selective anthracycline drugs indicate that the 3D chromatin organization is disrupted. Furthermore, AML patients receiving anthracycline drugs showed altered chromatin structures around potential looping anchors, which linked to distinct clinical outcomes. Our data indicate that anthracyclines are potent and selective epigenomic targeting drugs and can target the 3D genome for anticancer therapy, which could be used for personalized medicine to treat tumors with aberrant 3D chromatin structures.

The annual number of human leukocyte antigen (HLA)-haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HCT) is increasing steadily. Comparative studies about haplo-HCT versus HCT with HLA-matched sibling donors (MSD-HCT) have been tried in acute myeloid leukemia and B-cell acute lymphoblastic leukemia/lymphoma (ALL). Few studies were reported in adult T-cell ALL (T-ALL). In this retrospective study, a total of 88 consecutive patients with T-ALL were enrolled who underwent MSD-HCT ( n = 24) and haplo-HCT ( n = 64) with antithymocyte globulin (ATG)-based graft versus host disease (GVHD) prophylaxis between 2010 and 2022. Median follow-up for survivors was similar (43.5 [range: 7-88] months for MSD-HCT versus 43.5 (range: 6-144) months in the Haplo-HCT group). The 100-day cumulative incidence of grade II to IV acute GVHD (aGVHD) was similar, 33% (95% confidence interval [CI], 16%-52%) after MSD-HCT versus 44% (95% CI, 31%-55%) after haplo-HCT, P = 0.52. The cumulative incidences of grade III-IV aGVHD were 8% (95% CI, 1%-23%) in the MSD-HCT group and 5% (95% CI, 1%-12%) in the haplo-HCT group ( P = 0.50). The 2-year cumulative incidence of chronic GVHD (limited and extensive) in the haplo-HCT, 11% (95% CI, 5%-20%) was significantly lower than that in the MSD-HCT group (42% [95% CI, 21%-62%], P = 0.002). The cumulative incidence of 4-year relapse rates (44% versus 37%, P = 0.56) and non-relapse mortality (7% versus 21%, P = 0.08) did not differ between these two groups. There were also no differences in 4-year overall survival (46% versus 47%, P = 0.44) and progression-free survival (49% versus 42%, P = 0.45) between these two groups. On multivariate analysis, using busulfan/fludarabine (BU/Flu) conditioning regimen was found to be associated with worse clinical outcome. Our results suggested that ATG-based haplo-HCT platform could work as an alternative to MSD-HCT for adult patients with T-ALL. Compared with MSD-HCT, haplo-HCT might carry a low risk for cGVHD., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.