Dataset Information

Project title: Effect of FHD-286 or BRG1/BRM degrader AU15330 on protein expressions in MLL1-rearranged AML cells

ABSTRACT: MOLM13 cells and patient-derived de novo AML cells with MLL1 rearrangement were treated with 100 nM of FHD-286 or 100 nM of AU15330, a dual BRG1/BRM protein degrader for 48 hours. The goal was to determine the global protein expression alterations that correlate with the cell cycle, growth inhibitory and/or lethal effects of treatment with a chromatin remodeling inhibitor, FHD-286, or a BRG1/BRM protein degrader in MLL1-rearranged AML cells.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Antrix Jain

LAB HEAD: Kapil N. Bhalla

PROVIDER: PXD055994 | Pride | 2025-04-28

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	54306_1_ECL_1204_hs_TMT16_prof_250ng_F01.pepXML	Pepxml
	54306_1_ECL_1204_hs_TMT16_prof_250ng_F01.raw	Raw
	54306_1_ECL_1204_hs_TMT16_prof_250ng_F02.pepXML	Pepxml
	54306_1_ECL_1204_hs_TMT16_prof_250ng_F02.raw	Raw
	54306_1_ECL_1204_hs_TMT16_prof_250ng_F03.pepXML	Pepxml

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Publications

Superior preclinical efficacy of co-treatment with BRG1/BRM and FLT3 inhibitor against AML cells with FLT3 mutations.

Fiskus Warren W Mill Christopher P CP Piel Jessica J Collins Mike M Hentemann Murphy M Cuglievan Branko B Birdwell Christine E CE Das Kaberi K Hou Hanxi H Davis John A JA Jain Antrix A Malovannaya Anna A Kadia Tapan M TM Daver Naval N Sasaki Koji K Takahashi Koichi K Hammond Danielle D Reville Patrick K PK Flores Lauren B LB Loghavi Sanam S Su Xiaoping X DiNardo Courtney D CD Bhalla Kapil N KN

Blood cancer journal 20250315 1

Although treatment with standard frontline therapies, including a FLT3 inhibitor (FLT3i) reduces AML burden and achieves clinical remissions, most patients with AML with FLT3 mutation relapse due to therapy-resistant stem/progenitor cells. The core ATPases, BRG1 (SMARCA4) and BRM (SMARCA2) of the canonical (c) BAF (BRG1/BRM-associated factor) complex is a dependency in AML cells, including those harboring FLT3 mutations. We have previously reported that treatment with FHD-286, a BRG1/BRM ATPases ...[more]

PMID: 40089460

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Project description:The two catalytic subunits of the SWI/SNF chromatin remodeling complex - Brg1 and Brm - have been often implicated as essential components of common biological processes, suggesting a functional redundancy between these two proteins. For instance, earlier works indicated that both proteins are required for the activation of the myogenic program. However, their mutually exclusive pattern of incorporation in SWI/SNF complexes with variable composition and functional heterogeneity predicts that Brg1- and Brm-based SWI/SNF complexes execute specific functions to coordinate gene expression in multistep programs, such as skeletal myogenesis. We detected a distinct expression profile of Brg1 and Brm during the myogenic program, with Brm being upregulated in differentiating myocytes. Genetic knockdown of either Brg1 or Brm in skeletal myoblasts, followed by gene expression analysis, revealed discrete functions during myogenic differentiation. While Brm is required for the exit from the cell cycle at the early stages of differentiation, by repressing CyclinD1 transcription, Brg1 is required for the activation of muscle gene transcription. Interestingly, at later stages of differentiation Brg1 and Brm cooperate to the activation of a cluster of common target genes. Thus, Brg1 and Brm appear to coordinate activation and repression of distinct subsets of genes during initial phase myogenesis, and converge to cooperatively activate the expression of muscle genes at later stages. C2C12 myoblasts treated with siBRM or siBRG1 or siSCR in growth medium (GM) and differentiated by medium replacemnte (DM ). Celles were collected at 18h and 48h from the onset of DM for RNA extraction and microarray analysis. Arrays were used to generate 6 data sets in duplicate.To address the question of which genes were regulated by BRM and/or BRG1 the fold changes in gene expression were calculated between Scrambled siRNA and the BRM or BRG1 siRNA. The experiments were repeated at 2 different time points (18 hours and 48 hours) .