Dependence on Myb expression is attenuated in myeloid leukaemia with N-terminal CEBPA mutations

Volpe, Giacomo; Cauchy, Pierre; Walton, David S.; Ward, Carl; Blakemore, Daniel; Bayley, Rachael; Clarke, Mary L.; Schmidt, Luisa; Nerlov, Claus; García, Paloma; Dumon, Stéphanie; Grebien, Florian; Frampton, Jon

doi:10.26508/lsa.201800207

Cited by 6 publications

(2 citation statements)

References 50 publications

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“…Chromatin binding of the transcription factor MYB, which is often de-regulated in leukemia at p30-specific sites was correlated with activated transcription, while the expression of genes in the proximity of regions bound by MYB together with p42 was predominantly repressed. [ 45 ] These data point toward specific generegulatory functions of p30 that result in aberrant gene expression and oncogenic transformation.…”

Section: C/ebp α P30-a Gain-of-function Variant?mentioning

confidence: 99%

Gain‐of‐Function Effects of N‐Terminal CEBPA Mutations in Acute Myeloid Leukemia

2019

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Mutations in theCEBPA gene are present in 10-15% of acute myeloid leukemia (AML) patients. The most frequent type of mutations leads to the expression of an N-terminally truncated variant of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBP ), termed p30. While initial reports proposed that p30 represents a dominant-negative version of the wild-type C/EBP protein, other studies show that p30 retains the capacity to actively regulate gene expression. Recent global transcriptomic and epigenomic analyses have advanced the understanding of the distinct roles of the p30 isoform in leukemogenesis. This review outlines direct and indirect effects of the C/EBP p30 variant on oncogenic transformation of hematopoietic progenitor cells and discusses how studies of N-terminal CEBPA mutations in AML can be extrapolated to identify novel gain-of-function features in oncoproteins that arise from recurrent truncating mutations in transcription factors.

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Section: C/ebp α P30-a Gain-of-function Variant?mentioning

confidence: 99%

Gain‐of‐Function Effects of N‐Terminal CEBPA Mutations in Acute Myeloid Leukemia

2019

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“…Menin was found to be essential for transformation and maintenance of KMT2A -rearranged leukemias [ 27 , 28 ] and our previous findings suggest that endogenous Kmt2a is required for MN1-driven leukemia [ 19 ]. Interestingly, the Menin/KMT2A interaction has also been found to be required in other subtypes of leukemia such as those with NPM1c [ 41 ] and C/EBPα mutations [ 42 , 43 ]. Therefore, we next investigated whether the Kmt2a N-terminal interaction partner Menin was required in MN1-driven leukemia.…”

Section: Resultsmentioning

confidence: 99%

Menin is necessary for long term maintenance of meningioma-1 driven leukemia

et al. 2021

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Translocations of Meningioma-1 (MN1) occur in a subset of acute myeloid leukemias (AML) and result in high expression of MN1, either as a full-length protein, or as a fusion protein that includes most of the N-terminus of MN1. High levels of MN1 correlate with poor prognosis. When overexpressed in murine hematopoietic progenitors, MN1 causes an aggressive AML characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2A-rearranged (KMT2A-r) leukemia, including high levels of Hoxa and Meis1 gene expression. Compounds that target a critical KMT2A–Menin interaction have proven effective in KMT2A-r leukemia. Here, we demonstrate that Menin (Men1) is also critical for the self-renewal of MN1-driven AML through the maintenance of a distinct gene expression program. Genetic inactivation of Men1 led to a decrease in the number of functional leukemia-initiating cells. Pharmacologic inhibition of the KMT2A–Menin interaction decreased colony-forming activity, induced differentiation programs in MN1-driven murine leukemia and decreased leukemic burden in a human AML xenograft carrying an MN1-ETV6 translocation. Collectively, these results nominate Menin inhibition as a promising therapeutic strategy in MN1-driven leukemia.

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The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

et al. 2021

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Mutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.

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Dependence on Myb expression is attenuated in myeloid leukaemia with N-terminal CEBPA mutations

Cited by 6 publications

References 50 publications

Gain‐of‐Function Effects of N‐Terminal CEBPA Mutations in Acute Myeloid Leukemia

Gain‐of‐Function Effects of N‐Terminal CEBPA Mutations in Acute Myeloid Leukemia

Menin is necessary for long term maintenance of meningioma-1 driven leukemia

The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

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