c-Myb binds MLL through menin in human leukemia cells and is an important driver of MLL-associated leukemogenesis

Jin, Shenghao; Zhao, Helen; Yan, Ye; Nakata, Yuji; Kalota, Anna; Gewirtz, Alan M.

doi:10.1172/jci38030

Cited by 113 publications

(103 citation statements)

References 78 publications

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“…Thus, the putative repressor interacting with the SIM in TAD must play a particularly important role. Interestingly, the two factors p300 and MLL, shown to be necessary for promoting transformation by c-Myb, bind within the same region (Pattabiraman et al, 2009;Jin et al, 2010). Thus, our data on SUMO binding add to the complexity and functional importance of the transactivation domain in c-Myb.…”

Section: Discussionmentioning

confidence: 65%

“…Furthermore, the double mutant ANAA 2KR was hyperactive in transactivation assays but was only marginally more active than ANAA in transforming the FDB1 cells (Figure 7). This is surprising because there is generally strong correlation between transactivation and transformation by c-Myb (Hu et al, 1991), and the importance of functional co-activation by CBP/p300 (Pattabiraman et al, 2009) and menin/MLL (Jin et al, 2010) has been shown. In cancers linked to aberrations involving the MYB locus, increased c-Myb dosage, and hence activity, seems to be a common theme (Clappier et al, 2007;Lahortiga et al, 2007;Persson et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the transcriptional regulatory activity of Myb is crucial for its transforming ability (Gonda et al, 1989;Lane et al, 1990;Hu et al, 1991). Multiple co-factors like p300/CBP, Mi-2a, FLASH and menin/MLL engage in the regulation of the transactivational activity of c-Myb (Dai et al, 1996;Oelgeschlager et al, 1996;Kasper et al, 2002;Saether et al, 2007;Alm-Kristiansen et al, 2008;Jin et al, 2010). Recently, the importance of coactivation by p300 in myeloid transformation was highlighted using a novel murine hematopoietic cell line transformation assay (Pattabiraman et al, 2009).…”

mentioning

confidence: 99%

“…Recently, the importance of coactivation by p300 in myeloid transformation was highlighted using a novel murine hematopoietic cell line transformation assay (Pattabiraman et al, 2009). Moreover, the interaction between Myb and menin/MLL has been shown to be a critical driver in MLL-associated leukemogenesis (Jin et al, 2010).…”

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confidence: 99%

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A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

et al. 2010

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

et al. 2010

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“…H3K4 methylation is primarily localized in the promoter and regulatory regions of genes. Some transcription factors, such as Menin, LEDGF, HCF1/2, E2F, NFE2, p53, and c-Myb, have been shown to interact with MLL family members, which could lead to methylation of H3K4 in a locus-or DNA sequence-specific manner [16,17,[25][26][27][28][29]. A recent study by our group identified a physical and functional interaction between RUNX1 and MLL, and showed that both are required for maintenance of the H3K4me3 mark at two critical regulatory regions of the RUNX1 target gene PU.1 locus [30].…”

Section: Mll and Its Role In Normal Hematopoiesismentioning

confidence: 99%

Disordered epigenetic regulation in MLL-related leukemia

et al. 2012

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Leukemias bearing rearrangements of chromosome 11q23 are of particular interest due to their unique clinical and biological characteristics. 11q23 abnormalities occur in up to 70 % of infant leukemias, and about 10 % of adult acute myelogenous leukemias (AML). Two major rearrangements of the MLL gene are found in MLL-related leukemia. The most common of these is balanced translocations in which the N-terminal portion of MLL is fused to the C-terminus of the translocation partner. To date, nearly 100 different chromosome bands have been described in rearrangements involving MLL, and more than 70 known fusion partners of MLL have been cloned and characterized at the molecular level. Another major aberration of the MLL gene creates a repeat within the N-terminal MLL resulting in an internal partial tandem duplication (PTD). As a consequence, an extra amino-terminus is added in-frame to full-length MLL, resulting in leukemogenic MLL-PTD. MLL-PTD occurs predominantly in myeloid dysplasia syndromes, secondary AML (s-AML), and de novo AML. The presence of an MLL rearrangement generally confers a poor prognosis. MLL fusions and MLL-PTD are transcriptional regulators that take control of targets normally controlled by MLL, with the clustered HOX homeobox genes as prominent examples. Several epigenetic regulators that modify DNA or histones have been implicated in MLL fusion driven leukemogenesis, including DNA methylation, histone acetylation, and histone methylation. Recently, the histone methyltransferase DOT1L, the bromodomain and extra-terminal (BET) family member BRD4, and the MLL-interacting protein Menin have emerged as important mediators of MLL fusion-mediated leukemic transformation. The clinical development of targeted inhibitors of these epigenetic regulators has heralded promise for the treatment of MLL fusion leukemia. Although the biological function and molecular mechanism for MLL-PTD remains largely unknown, based on the primary protein structure of MLL-PTD and the knowledge gained so far from MLL fusions, newly developed inhibitors of epigenetic regulators could potentially also prove effective in the treatment of MLL-PTD related leukemias.

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Dissecting the transactivation domain (tAD) of the transcription factor c‐Myb to assess recent models of tAD function

et al. 2020

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Genes are activated by transcription factors through their transactivation domains (tADs); disordered regions that have been poorly understood. New models for tADs have recently been proposed. Here, these models were assessed through a mutational analysis of the tAD of the master regulator c‐Myb. Analysis in mammalian cells strongly supported the ‘SLM‐exposure model’. In yeast, tAD mutants behaved quite differently.

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c-Myb binds MLL through menin in human leukemia cells and is an important driver of MLL-associated leukemogenesis

Cited by 113 publications

References 78 publications

A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

Disordered epigenetic regulation in MLL-related leukemia

Dissecting the transactivation domain (tAD) of the transcription factor c‐Myb to assess recent models of tAD function

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