MBNL1 hijacks a structured single-stranded distal DNA element to sustain FLT3 expression in KMT2A-rearranged leukemias
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE263684 | GEO | 2026/06/10
REPOSITORIES: GEO
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Project description:Activating FLT3 and RAS mutations are common in KMT2A-rearrangement (KMT2A-r) leukemia, but their functions in remodeling the chromatin accessibility is unknow. Using a retroviral acute myeloid leukemia (AML) mouse model driven by KMT2A::MLLT3, we show that FLT3/ITD, FLT3/N676K, and NRAS/G12D rewired the chromatin accessibility landscape and associated transcriptional networks. FLT3/N676K and NRAS/G12D mutations resulted in similar networks which were distinct from those mediated by FLT3/ITD. Motif analysis revealed that the AP-1 family transcription factors had a role in KMT2A::MLLT3 leukemia with FLT3/N676K and NRAS/G12D, whereas RUNX1/2 and Stat5a/Stat5b were active in the presence of FLT3/ITD. Further, transcriptional programs related with stemness, activation of T-cells and negative regulation of NK-cells were activated in the presence of NRAS/G12D and FLT3/N676K. Taken together, activating mutations established mutation-specific changes in the epigenetic landscape that led to changes in the transcriptional programs driven by specific transcription factors.
2024-09-01 | GSE248468 | GEO
Project description:Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements. Herein, we show that co-expression of FLT3-N676K and KMT2A-MLLT3 in human CD34+ cord blood cells primarily cause acute myeloid leukemia (AML) and rarely acute lymphoblastic leukemia (ALL) in immunodeficient mice. By contrast, expression of KMT2A-MLLT3 alone cause ALL, double-positive leukemia (DPL, expressing both CD33 and CD19), or bilineal leukemia (BLL, comprised of distinct myeloid and lymphoid leukemia cells), and rarely AML. Further, AML could only be serially propagated with maintained immunophenotype in secondary recipients when cells co-expressed KMT2A-MLLT3 and FLT3-N676K. Consistent with the idea that activated signaling would allow myeloid cells to engraft and maintain their self-renewal capacity, in a secondary recipient, a de novo KRAS-G13D was identified in myeloid cells previously expressing only KMT2A-MLLT3. Gene expression profiling revealed that KMT2A-MLLT3 DPL had a highly similar gene expression profile to ALL, with both expressing key lymphoid transcription factors and ALL cell surface markers, in line with the DPL cells being ALL cells with aberrant expression of CD33. Taken together, our results highlight the need for constitutive active signaling mutations for driving myeloid leukemia in a human xenograft model of KMT2A-R acute leukemia.
2019-04-05 | GSE127492 | GEO
Project description:In order to identify MBNL1-dependent changes in MBNL1 target transcript stability, MBNL1 levels in MDA-MB-231 breast cancer cells were stably knocked-down using short-hairpin RNAs. The cells were then treated with alpha-amanitin to inhibit transcription, RNA was isolated at 0 and 9 hours post-alpha-amanitin treatment, and the samples were transcriptomically profiled.
2016-10-14 | GSE76485 | GEO
Project description:Activating mutations in kinase/PI3K/RAS signaling pathways are common in acute leukemia with KMT2A rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remain unclear. Using a retroviral acute myeloid leukemia model, we demonstrate that NRASG12D, FLT3ITD, and FLT3N676K accelerates KMT2A-MLLT3 leukemia onset. Importantly, also the presence of subclonal FLT3N676K in KMT2A-R leukemic cells shorten disease latency, possibly by providing stimulatory factors such as Mif. Acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 were identified in KMT2A-MLLT3 driven leukemia and favored clonal expansion. KMT2A-MLLT3 leukemia with an activating mutation enforce Myc- and Myb transcriptional modules, whereas KMT2A-MLLT3 leukemias lacking activating mutations displayed upregulation of signal transduction pathways. Our results provide new insight into the biology of KMT2A-R leukemia and highlights the importance of activated signaling as a contributing driver in this disease.
2018-05-02 | PXD008213 | Pride
Project description:CUG-binding protein 1 (CUGBP1) and muscleblind-like 1 (MBNL1) are developmentally regulated RNA-binding proteins that are causally associated with myotonic dystrophy type 1. We extensively determined RNA-binding sites of CUGBP1 and MBNL1 to investigate their roles in RNA processing. We also analyzed polypyrimidine tract-binding protein (PTB) as a control. CUGBP1 and MBNL1 preferentially bind to alternatively spliced introns and exons, respectively, and regulate alternative splicing events. Moreover, CUGBP1 and MBNL1 are preferentially bound to the 3' untranslated regions (UTRs), in particular of genes for RNA-binding proteins, and facilitate decay of the bound mRNAs. In addition, CUGBP1 and MBNL1 mutually destabilize mRNA. Precise temporal regulation of CUGBP1 and MBNL1 are likely to be essential for accurate control of destabilization of a broad spectrum of genes as well as of alternative splicing events in cell differentiation and tissue development.
2012-01-04 | E-MTAB-414 | biostudies-arrayexpress
Project description:In this study, we identify MBNL1 as a unique molecular vulnerability across MLL-rearranged leukemias. Through transcriptomic profiling and novel splicing analyses of MLL-rearranged leukemia cell lines following shRNA knockdown of MBNL1, we show that MBNL1 regulates alternative splicing (predominantly intron retention) of genes essential to MLL-rearranged leukemogenesis, such as DOT1L and SETD1A.
2020-03-25 | GSE123441 | GEO
Project description:The differentiation of fibroblasts into myofibroblasts mediates tissue wound healing and fibrotic remodeling. To better understand this process we performed a genome-wide screen in fibroblasts, which identified the RNA-binding protein muscleblind-like 1 (MBNL1) as a potent regulator of myofibroblast differentiation. MBNL1 promoted transformation of fibroblasts into myofibroblasts, while loss of Mbnl1 abrogated myofibroblast differentiation and impaired the fibrotic phase of wound healing in mouse models of myocardial infarction and dermal injury. Conditional fibroblast-specific MBNL1 transgenic mice showed a fibrotic phenotype in the absence of injury. Mechanistically, MBNL1 directly bound to and regulated the alternative splicing and stability of a network of myofibroblast differentiation specific genes, such as the nodal transcriptional regulator serum response factor (SRF). CRISPR-Cas9 mediated gene editing of the MBNL1 binding site in Srf impaired myofibroblast differentiation. These data establish a new RNA-dependent paradigm through MBNL1 that underlies global myofibroblast differentiation, the fibrotic response, and tissue wound healing.
2015-10-20 | GSE74185 | GEO
Project description:Background: Discovering determinants of cardiomyocyte maturity will be critical to understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Recent evidence has suggested that forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration. However, elucidation of endogenous developmental determinants of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. Muscleblind-like 1 (MBNL1) regulates both fibroblast and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. Methods: MBNL1 gain- and loss-of-function mouse models were studied at several developmental timepoints and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro genetic work to determine the mechanisms through which MBNL1 exerts its effects. Results: MBNL1 is co-expressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/Calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, while loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration, and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deletion was not sufficient to promote regeneration in the adult heart due to cell-cycle checkpoint activation. Conclusions: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Additionally, MBNL1-dependent perturbations of a myocyte’s preferred growth mechanism at a given developmental state had detrimental consequences to cardiac function, and targeting loss of maturity and removing cell cycle inhibitors was not insufficient to promote adult regeneration.
2024-03-07 | GSE246742 | GEO
Project description:Background: Discovering determinants of cardiomyocyte maturity will be critical to understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Recent evidence has suggested that forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration. However, elucidation of endogenous developmental determinants of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. Muscleblind-like 1 (MBNL1) regulates both fibroblast and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. Methods: MBNL1 gain- and loss-of-function mouse models were studied at several developmental timepoints and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro genetic work to determine the mechanisms through which MBNL1 exerts its effects. Results: MBNL1 is co-expressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/Calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, while loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration, and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deletion was not sufficient to promote regeneration in the adult heart due to cell-cycle checkpoint activation. Conclusions: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Additionally, MBNL1-dependent perturbations of a myocyte’s preferred growth mechanism at a given developmental state had detrimental consequences to cardiac function, and targeting loss of maturity and removing cell cycle inhibitors was not insufficient to promote adult regeneration.
2024-03-07 | GSE246740 | GEO
Project description:Background: Discovering determinants of cardiomyocyte maturity will be critical to understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Recent evidence has suggested that forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration. However, elucidation of endogenous developmental determinants of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. Muscleblind-like 1 (MBNL1) regulates both fibroblast and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. Methods: MBNL1 gain- and loss-of-function mouse models were studied at several developmental timepoints and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro genetic work to determine the mechanisms through which MBNL1 exerts its effects. Results: MBNL1 is co-expressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/Calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, while loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration, and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deletion was not sufficient to promote regeneration in the adult heart due to cell-cycle checkpoint activation. Conclusions: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Additionally, MBNL1-dependent perturbations of a myocyte’s preferred growth mechanism at a given developmental state had detrimental consequences to cardiac function, and targeting loss of maturity and removing cell cycle inhibitors was not insufficient to promote adult regeneration.
2024-03-07 | GSE246741 | GEO