Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation

Abstract

Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cell types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 Mb downstream from Myc that are occupied by SWI/SNF as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in~3% of acute myeloid leukemias. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs.

Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia

“…This region interacts with the MYC promoter in small lymphocytic lymphoma and mantle cell lymphoma, and also leads to MYC transcriptional activation in Epstein-Barr-transformed lymphoblastoid cells as a result of Epstein-Barr virus nuclear antigen 2 binding (52,62). The focal recurrent duplications of this locus observed in CLL (7,53), analogous to what is observed in other malignancies in which CN gains affect the tissue-specific enhancers involved in MYC expression (50,63,64), suggest that the gain of context-specific superenhancers represents a common mechanism for up-regulating MYC expression in distinct tumor types. However, the detection of this superenhancer cluster also in CLL cases devoid of ICN1 expression (Fig.…”

SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells

“…Super-enhancers are mostly associated with developmentally regulated genes. SMARCA4 is localized at super-enhancers in leukemic and in normal B-cells (Shi et al 2013;Bossen et al 2015). Using the approach previously published , we identified 109 SMARCA4-bound superenhancers in the MCF-10A genome (Fig.…”

Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes

“…While several studies have noted the association between BRD4 and BRG1 (45), it has not been clear how they might be functionally related in cancer. For example, AML is dependent on both BRD4 (46,47) and BRG1 (43,47) however, their roles in AML transcriptional regulation are very different, making it difficult to determine the functional relevance of this association. We find that the association between BRD4 and BRG1 is specific to GLTSCR1, which will provide a framework for deciphering the functional relevance of this association in both the normal and cancer setting.…”