MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model

Abstract

Although the mixed lineage leukemia 5 (MLL5) gene has prognostic implications in acute promyelocyte leukemia (APL), the underlying mechanism remains to be elucidated. Here, we demonstrate the critical role exerted by MLL5 in APL regarding cell proliferation and resistance to drug-induced apoptosis, through mtROS regulation. Additionally, MLL5 overexpression increased the responsiveness of APL leukemic cells to all-trans retinoic acid (ATRA)-induced differentiation, via regulation of the epigenetic modifiers SETD7 and LSD1. In silico analysis indicated that APL blasts with MLL5high transcript levels were associated with retinoic acid binding and downstream signaling, while MLL5low blasts displayed decreased expression of epigenetic modifiers (such as KMT2C, PHF8 and ARID4A). Finally, APL xenograft transplants demonstrated improved engraftment of MLL5-expressing cells and increased myeloid differentiation over time. Concordantly, evaluation of engrafted blasts revealed increased responsiveness of MLL5-expressing cells to ATRA-induced granulocytic differentiation. Together, we describe the epigenetic changes triggered by the interaction of MLL5 and ATRA resulting in enhanced granulocytic differentiation.

M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism

“…Recombinant lentivirus encoding FLT3 -ITD, NPM1 cyt, and BCR-ABL fusion p210, overexpression of MN1 , and the KD of DNMT3A (DNMT3A-KD) were generated using different lentiviral backbone plasmids as described in the resource table. Virus was produced in human embryonic kidney–293T cells according to the three-plasmid packaging procedure as described elsewhere ( 70 ). Lentiviral particles were concentrated using Amicon Ultra-15 centrifugal filter unit columns (Merck, CA, USA).…”

Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension

“…23 aging institute, University of Pittsburgh, Pittsburgh, Pa 15219, USa. 24 research computing, arizona State University, Tempe, aZ 85281, USa. 25 department of Pharmacology and chemical Biology, University of Pittsburgh, Pittsburgh, Pa 15213, USa.…”

Lysine-Specific Demethylase 1 Promises to Be a Novel Target in Cancer Drug Resistance: Therapeutic Implications

“…104 Besides, enhanced expression of MLL5 improved the ATRA-driven therapeutic response in APL, and MLL5 might mediate the suppression of LSD1 with dependent on ATRA and partly regulated the epigenome to promote sensibility to drugs. 102,108 Moreover, LSD1i could promote response of sAML cells to ruxolitinib or BETi through reprogramming of SEs/Es and modifying gene expression concerning nongenetic-resistance. 103 As illustrated in Figure 4b, in addition to blocking the axis of LSD1 and CoREST/growth factor independent 1 (GFI1), downregulation of LSD1 reduced c-Myc level, and induced the expression of CD11b, p21, PU.1, and GFI1, thereby repressing growth in vitro and inducing differentiation/apoptosis.…”

“…Drug resistance is increasingly recognized in AML, but there still have long way to overcome nongenetic therapy-resistance. In recent years, a few articles have reported the involvement of LSD1 in the regulation of resistance or resensitization of drug-resistant cells in AML. − GSK-LSD1 could recover sensitivity of resistant cells to IBET by a time-dependent modulation and overcome stable epigenetic resistance. The potential mechanism was that followed with LSD1 inhibition; the pioneer factor, purine-rich nucleic acid binding protein 1 (Pu.1), was stabilized by cofactor, interferon regulatory factor 8 (Irf8), to gain new enhancers, which combined with transcriptional coactivators containing BRD4, and then BRD4 was redisplaced by IBET to repress the transcription of genes crucial to the survival of the cells, as shown in Figure a .…”

“…In addition, general control nonderepressible 5 (GCN5) caused resistance to all-trans retinoic acid (ATRA) through abnormal acetylation of H3K9ac in non-APL AML, thereby sustaining stemness and leukemia-related genes expression. , At the same time, suppression of GCN5 unlocked the ATRA-driven therapeutic response, and inhibition of GCN5 and LSD1 by epigenetic reprogramming had synergistic effects in non-APL AML . Besides, enhanced expression of MLL5 improved the ATRA-driven therapeutic response in APL, and MLL5 might mediate the suppression of LSD1 with dependent on ATRA and partly regulated the epigenome to promote sensibility to drugs. , Moreover, LSD1i could promote response of sAML cells to ruxolitinib or BETi through reprogramming of SEs/Es and modifying gene expression concerning nongenetic-resistance . As illustrated in Figure b, in addition to blocking the axis of LSD1 and CoREST/growth factor independent 1 (GFI1), downregulation of LSD1 reduced c-Myc level, and induced the expression of CD11b, p21, PU.1, and GFI1, thereby repressing growth in vitro and inducing differentiation/apoptosis.…”