The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia

Numata, Akihiko; Kwok, Hui Si; Kawasaki, Akira; Li, Jia; Zhou, Qi; Kerry, Jon; Benoukraf, Touati; Bararia, Deepak; Li, Feng; Ballabio, Erica; Tapia, Marta; Deshpande, Aniruddha J.; Welner, Robert S.; Delwel, Ruud; Yang, Henry; Milne, Thomas A.; Taneja, Reshma; Tenen, Daniel G.

doi:10.1038/s41467-018-03854-0

Cited by 21 publications

(15 citation statements)

References 63 publications

(93 reference statements)

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“…1E) MBNL1 was recently demonstrated to be a direct target of the MLL-AF4 fusion protein in patientderived ALL cell lines as well as in an experimental retroviral model 20,29 . To determine whether this observation applied to leukemia cells bearing different MLL-fusion partners, we analyzed MLL-fusion protein (MLL-N and fusion partner C-terminus if applicable) and H3K79me2 chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) datasets from THP-1 30 and ML-2 31 cell lines (with MLL-AF9 and MLL-AF6 respectively), as well as from the MV4;11 30 , RS4;11 32 , and SEM 33 cell lines which bear an MLL-AF4 fusion. We found evidence of MLL-N/fusion-C binding to the MBNL1 promoter and gene body, along with H3K79me2 enrichment across all cell lines studied (Fig.…”

Section: Resultsmentioning

confidence: 99%

MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia

et al. 2020

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Despite growing awareness of the biologic features underlying MLL-rearranged leukemia, targeted therapies for this leukemia have remained elusive and clinical outcomes remain dismal. MBNL1, a protein involved in alternative splicing, is consistently overexpressed in MLL-rearranged leukemias. We found that MBNL1 loss significantly impairs propagation of murine and human MLL-rearranged leukemia in vitro and in vivo. Through transcriptomic profiling of our experimental systems, we show that in leukemic cells, MBNL1 regulates alternative splicing (predominantly intron exclusion) of several genes including those essential for MLL-rearranged leukemogenesis, such as DOT1L and SETD1A. We finally show that selective leukemic cell death is achievable with a small molecule inhibitor of MBNL1. These findings provide the basis for a new therapeutic target in MLL-rearranged leukemia and act as further validation of a burgeoning paradigm in targeted therapy, namely the disruption of cancer-specific splicing programs through the targeting of selectively essential RNA binding proteins.

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Section: Resultsmentioning

confidence: 99%

MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia

et al. 2020

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“…It was previously reported that Bhlhe40 and Bhlhe41 function predominantly as transcriptional repressors in many (Ow et al, 2014) but possibly not all (Numata et al, 2018) cellular contexts. In line with the repressive function of these transcription factors in AMs, gene set enrichment analysis (GSEA) demonstrated that genes associated with Bhlhe40 peaks were enriched among genes upregulated in DKO AMs (Figs 5E and EV4B).…”

Section: Broad Footprint Of Bhlhe40/bhlhe41 Deficiency On the Am Tranmentioning

confidence: 98%

Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self‐renewal and identity

et al. 2019

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Tissues in multicellular organisms are populated by resident macrophages, which perform both generic and tissue‐specific functions. The latter are induced by signals from the microenvironment and rely on unique tissue‐specific molecular programs requiring the combinatorial action of tissue‐specific and broadly expressed transcriptional regulators. Here, we identify the transcription factors Bhlhe40 and Bhlhe41 as novel regulators of alveolar macrophages (AMs)—a population that provides the first line of immune defense and executes homeostatic functions in lung alveoli. In the absence of these factors, AMs exhibited decreased proliferation that resulted in a severe disadvantage of knockout AMs in a competitive setting. Gene expression analyses revealed a broad cell‐intrinsic footprint of Bhlhe40/Bhlhe41 deficiency manifested by a downregulation of AM signature genes and induction of signature genes of other macrophage lineages. Genome‐wide characterization of Bhlhe40 DNA binding suggested that these transcription factors directly repress the expression of lineage‐inappropriate genes in AMs. Taken together, these results identify Bhlhe40 and Bhlhe41 as key regulators of AM self‐renewal and guardians of their identity.

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“…It is possible that some other chromatin-bound factors mediate the interaction between MLL and AF4 through the TRX2 domain. It has been reported that the region containing the TRX2 domain also associates with SHARP1, which may be involved in interaction between MLL and AF4 (Numata et al, 2018). Although the MLL 5′ portion retains the TRX2 domain, it cannot activate transcription of Hoxa9 and transform myeloid progenitors without its fusion partner portion (Lavau et al, 1997; Slany et al, 1998; Okuda et al, 2017), indicating that AF4 bound with the TRX2 domain is transcriptionally inactive and needs to form an AEP complex with ENL on nearby chromatin to become functional (Figure 5C).…”

Section: The Role Of Trx2 Domain Of Mllmentioning

confidence: 99%

RNA Polymerase II-Dependent Transcription Initiated by Selectivity Factor 1: A Central Mechanism Used by MLL Fusion Proteins in Leukemic Transformation

Yokoyama

2019

Front. Genet.

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Cancer cells transcribe RNAs in a characteristic manner in order to maintain their oncogenic potentials. In eukaryotes, RNA is polymerized by three distinct RNA polymerases, RNA polymerase I, II, and III (RNAP1, RNAP2, and RNAP3, respectively). The transcriptional machinery that initiates each transcription reaction has been purified and characterized. Selectivity factor 1 (SL1) is the complex responsible for RNAP1 pre-initiation complex formation. However, whether it plays any role in RNAP2-dependent transcription remains unclear. Our group previously found that SL1 specifically associates with AF4 family proteins. AF4 family proteins form the AEP complex with ENL family proteins and the P-TEFb elongation factor. Similar complexes have been independently characterized by several different laboratories and are often referred to as super elongation complex. The involvement of AEP in RNAP2-dependent transcription indicates that SL1 must play an important role in RNAP2-dependent transcription. To date, this role of SL1 has not been appreciated. In leukemia, AF4 and ENL family genes are frequently rearranged to form chimeric fusion genes with MLL. The resultant MLL fusion genes produce chimeric MLL fusion proteins comprising MLL and AEP components. The MLL portion functions as a targeting module, which specifically binds chromatin containing di-/tri-methylated histone H3 lysine 36 and non-methylated CpGs. This type of chromatin is enriched at the promoters of transcriptionally active genes which allows MLL fusion proteins to selectively bind to transcriptionally-active/CpG-rich gene promoters. The fusion partner portion, which recruits other AEP components and SL1, is responsible for activation of RNAP2-dependent transcription. Consequently, MLL fusion proteins constitutively activate the transcription of previously-transcribed MLL target genes. Structure/function analysis has shown that the ability of MLL fusion proteins to transform hematopoietic progenitors depends on the recruitment of AEP and SL1. Thus, the AEP/SL1-mediated gene activation pathway appears to be the central mechanism of MLL fusion-mediated transcriptional activation. However, the molecular mechanism by which SL1 activates RNAP2-dependent transcription remains largely unclear. This review aims to cover recent discoveries of the mechanism of transcriptional activation by MLL fusion proteins and to introduce novel roles of SL1 in RNAP2-dependent transcription by discussing how the RNAP1 machinery may be involved in RNAP2-dependent gene regulation.

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The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia

Cited by 21 publications

References 63 publications

MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia

MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia

Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self‐renewal and identity

RNA Polymerase II-Dependent Transcription Initiated by Selectivity Factor 1: A Central Mechanism Used by MLL Fusion Proteins in Leukemic Transformation

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