SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia

Chambers, Courtney; Čermáková, Kateřina; Chan, Yuen San; Kurtz, Kristen; Wohlan, Katharina; Lewis, Andrew Henry; Wang, Christiana; Pham, Anh; Dejmek, Milan; Šála, Michal; Cabrera, Mario Loeza; Aguilar, Rogelio; Nencka, Radim; Lacorazza, H. Daniel; Rau, Rachel E.; Hodges, H. Courtney

doi:10.1158/0008-5472.can-22-2129

Cited by 19 publications

(26 citation statements)

References 74 publications

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“…This resulted in 66 hits in THP-1 dCas9 cells and 169 in MOLM-13 dCas9 cells, with 63 of the identified hits shared between the two cell lines (Figs 1A and B,and EV1B,and Dataset EV2). Among the shared hits, there were multiple common essential genes, and several factors previously reported to sustain the proliferation of leukemic cells (e.g., KDM1A, MEN1, PRMT5, and SWI/SNF complex components) (Yokoyama et al, 2004;Caslini et al, 2007;Shi et al, 2013;Cruickshank et al, 2015;Radzisheuskaya et al, 2019;Ravasio et al, 2020;Rago et al, 2022;Chambers et al, 2023). We focused the further investigation on BPTF (Figs 1C and EV1C) since it has not been previously studied in the context of AML.…”

Section: Bptf Is Required For the Proliferation Of Acute Myeloid Leuk...mentioning

confidence: 99%

An alternative NURF complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions

Radzisheuskaya,

Peña‐Rømer,

Lorenzini

et al. 2023

The EMBO Journal

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Efficient treatment of acute myeloid leukemia (AML) patients remains a challenge despite recent therapeutic advances. Here, using a CRISPRi screen targeting chromatin factors, we identified the nucleosome‐remodeling factor (NURF) subunit BPTF as an essential regulator of AML cell survival. We demonstrate that BPTF forms an alternative NURF chromatin remodeling complex with SMARCA5 and BAP18, which regulates the accessibility of a large set of insulator regions in leukemic cells. This ensures efficient CTCF binding and boundary formation between topologically associated domains that is essential for maintaining the leukemic transcriptional programs. We also demonstrate that the well‐studied PHD2‐BROMO chromatin reader domains of BPTF, while contributing to complex recruitment to chromatin, are dispensable for leukemic cell growth. Taken together, our results uncover how the alternative NURF complex contributes to leukemia and provide a rationale for its targeting in AML.

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Section: Bptf Is Required For the Proliferation Of Acute Myeloid Leuk...mentioning

confidence: 99%

An alternative NURF complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions

Radzisheuskaya,

Peña‐Rømer,

Lorenzini

et al. 2023

The EMBO Journal

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“…Integration of PRC2 sites in untransformed umbilical cord HSPCs with C/G fusion binding sites in leukemia- like cells identified MYCN as a target, indicating that MYC-family members play a more significant role in C/G AML than previously appreciated. ZBTB16, ZFPM1 and LMO2 are also C/G targets and DepMap dependencies, and may comprise a core regulatory circuit along with GATA-1 and GATA-2 in this subtype of AML as LMO2 does in other AMLs 18 . Single cell transcriptomic analyses of differentiating, untransduced cord blood cells found that many of these genes are already expressed in megakaryocyte progenitors, and that ZBTB16 and ZFPM1 are preferentially expressed in MEPs and GMPs.…”

Section: Discussionmentioning

confidence: 99%

“…The sensitivity to BRG1 inhibition has been ascribed to PU.1 (Sp1) 17,18 , however, in DepMap PU.1 is a neutral gene in M07e. Further, we observed apoptosis in response to BRG1 inhibition, while differentiation has been reported in other AMLs 18 . Thus, other BRG1 targets are likely mediating the sensitivity in C/G AML, including the C/G fusion itself.…”

Section: Discussionmentioning

confidence: 99%

“…4e, S4c). Encouraged by these dependency scores, we tested two highly selective, orally bioavailable inhibitors of the related ATPases BRG1/BRM, BRM-014 and FHD-286 in M07e and WSU-AML cell lines 17,18 . Both cell lines demonstrated sensitivity to these agents, with FHD-286 displaying IC50's of 5nM in WSU-AML and 49nM in M07e and BRM-014 showing IC50s of 22nM in WSU-AML and 117nM in M07e (Fig.…”

Section: Smarca4/brg1 Inhibition As a Therapeutic Vulnerability In C/...mentioning

confidence: 99%

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Chromatin Profiling of CBFA2T3-GLIS2 AMLs Identifies Key Transcription Factor Dependencies and BRG1 Inhibition as a Novel Therapeutic Strategy

Kaonis,

Smith,

Katiyar

et al. 2023

Preprint

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Oncogenic fusions involving transcription factors are present in the majority of pediatric leukemias; however, the context-specific mechanisms they employ to drive cancer remain poorly understood. CBFA2T3-GLIS2 (C/G) fusions occur in treatment-refractory acute myeloid leukemias and are restricted to young children. To understand how the C/G fusion drives oncogenesis we applied CUT&RUN chromatin profiling to an umbilical cord blood/endothelial cell (EC) co-culture model of C/G AML that recapitulates the biology of this malignancy. We find C/G fusion binding is mediated by its zinc finger domains. Integration of fusion binding sites in C/G-transduced cells with Polycomb Repressive Complex 2 (PRC2) sites in control cord blood cells identifies MYCN, ZFPM1, ZBTB16 and LMO2 as direct C/G targets. Transcriptomic analysis of a large pediatric AML cohort shows that these genes are upregulated in C/G patient samples. Single cell RNA-sequencing of umbilical cord blood identifies a population of megakaryocyte precursors that already express many of these genes despite lacking the fusion. By integrating CUT&RUN data with CRISPR dependency screens we identify BRG1/SMARCA4 as a vulnerability in C/G AML. BRG1 profiling in C/G patient-derived cell lines shows that the CBFA2T3 locus is a binding site. Treatment with clinically-available BRG1 inhibitors reduces fusion levels and downstream C/G targets including N-MYC, resulting in C/G leukemia cell death and extending survival in a murine xenograft model.

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“…Findings presented demonstrate that treatment with FHD-286 overcame differentiation block and significantly induced in vitro differentiation and loss of viability in AML cell lines and PD AML cells with MLL1r or mtNPM1 similar to those reported earlier (14,15). FHD-286-induced lethality was associated with marked perturbations in chromatin accessibility, inhibition of enhancers, core regulatory circuitry and gene expressions in the AML cells (2,7,16,17). Our findings also demonstrate in vivo efficacy of monotherapy with FHD-286, including depletion of leukemia-initiating AML stem-progenitor cells, reduction of AML burden and significant survival gains in PDX models of AML with MLL1r or mtNPM1 (14,15,18).…”

Section: Introductionmentioning

confidence: 99%

BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor

Fiskus,

Piel,

Collins

et al. 2023

Preprint

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BRG1 (SMARCA4) and BRM (SMARCA2) are the core ATPases of chromatin remodeling BAF (BRG1/BRM-associated factor) complexes, which enable transcription factors/co-factors to modulate gene-expressions, mediating growth, differentiation-arrest and survival of AML cells. In AML with MLL1r (MLL1 rearrangement) or mutant (mt) NPM1, although monotherapy with Menin inhibitor (MI) induces clinical remissions, most patients either fail to respond or relapse. FHD-286 is a selective BRG1/BRM inhibitor, undergoing clinical development in AML. Here, FHD-286 induced differentiation and lethality in AML cells with MLL1r or mtNPM1, reducing chromatin accessibility and repressing c-Myc, PU.1 and CDK4/6. Whereas FHD-286 monotherapy reduced AML burden, leukemia-initiating potential and improved survival, FHD-286 combinations with MI, BET inhibitor, decitabine or venetoclax was significantly more effective in reducing AML burden and improved survival, without significant toxicity, in xenograft models of AML with MLL1r or mtNPM1. These findings highlight promising FHD-286-based combinations for therapy of AML with MLL1r or mtNPM1.Statement of SignificanceInhibition of BRG1/BRM ATPases by FHD-286 reduced chromatin accessibility, repressed c-Myc, PU.1 and CDK4/6, inducing differentiation, leukemia-initiating potential and lethality in AML stem-progenitor cells. FHD-286-based combinations with Menin or BET inhibitor or decitabine reduced AML burden and improved survival in xenograft models of AML with MLL rearrangement or mutant NPM1.

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SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia

Cited by 19 publications

References 74 publications

An alternative NURF complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions

An alternative NURF complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions

Chromatin Profiling of CBFA2T3-GLIS2 AMLs Identifies Key Transcription Factor Dependencies and BRG1 Inhibition as a Novel Therapeutic Strategy

BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor

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