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MLL2, but not MLL1, plays a major role to sustain leukemia survival [array]

ABSTRACT: The MLL1 histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Here we show using rigorous, independent animal models that endogenous MLL1 is dispensable for MLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog, Mll2. Surprisingly, Mll2 deletion alone had a significant impact on survival of MLL-AF9-transformed cells and additional Mll1 loss further reduced viability and proliferation. We show that MLL1/MLL2 collaboration is not through redundancy but regulation of distinct pathways. These findings highlight the relevance of MLL2 as a drug target in MLL-rearranged leukemia and suggest its broader significance in AML. We used microarray to investigate the effect of Mll1 deletion on gene expression in LSC-enriched MLL-AF9 leukemia cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE93621 | GEO | 2017/01/20

SECONDARY ACCESSION(S): PRJNA362638

REPOSITORIES: GEO

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MLL2, but not MLL1, plays a major role to sustain leukemia survival [RNA-seq]

Project description:We investigated the effect of Mll1, Mll2 and Mll1;Mll2 deletion on gene expression in MLL-AF9-transformed cells.

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RNA sequencing expression analysis of murine MLL-AF9;NRAS acute myeloid leukemia cells silenced for E2-2.

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RNA sequencing expression analysis of murine MLL-AF9;NRAS acute myeloid leukemia cells silenced for E2-2.

Project description:We investigated the role of the transcriptional regulators Id2 and E2-2 (encoded by Tcf4) in the context of MLL-rearranged acute myeloid leukemia (AML). Using an AML mouse model driven by a Tet-off inducible MLL-AF9 allele co-expressed with oncogenic NRASG12D, we demonstrated that MLL-AF9 regulates the E protein pathway by suppressing Id2, while activating the expression of its target E2-2. Moreover, we found that Id2 over-expression in MLL-AF9 AML cells results inhibition of leukemia growth, loss of leukemia stem cell-associated gene expression pattern and induction of differentiation. E2-2 silencing phenocopies Id2 overexpression in MLL-AF9-AML cells. To study the gene expression changes associated with E2-2 depletion in the context of MLL-rearranged AML, RNA sequencing analysis was performed on MLL-AF9;NRAS AML cells transduced with vectors expressing hairpins against E2-2 (shTcf4#654 and shTcf4#3646) or a control hairpin against Renilla luciferase (shRen). Primary AMLs driven by MLL/AF9 expression linked to cherry reporter, in association with oncogenic NRASG12D (MLL/AF9;NRAS) were generated by reconstituting lethally irradiated congenic mice with fetal liver cells co-transduced with the MSCV-MLL/AF9-IRES-cherry retroviral vector and a second vector co-expressing NRASG12D together with luciferase (MSCV-luciferase-IRES-NRASG12D). RNA sequencing analysis sequencing analysis was performed on MLL-AF9;NRAS AML cells transduced in vitro with vectors expressing hairpins against E2-2 (shTcf4#654 and shTcf4#3646) or a control hairpin against Renilla luciferase (shRen) linked to the reporter GFP. Viable GFP-positive cells were FACS-sorted 2 days after transduction and used for RNA sequencing analysis. Two independent biological replicates of the experiment were used for the RNA sequencing (9-5-14 and 14-4-14).

2016-06-29 | E-GEOD-80745 | biostudies-arrayexpress

MLL2, but not MLL1, plays a major role to sustain leukemia survival

Project description:MLL2, but not MLL1, plays a major role to sustain leukemia survival

| PRJNA362633 | ENA

Regulation of transcription by MLL2 complex and MLL complexes-associated protein AKAP95

Project description:Although histone H3 lysine 4 (H3K4) methylation is widely associated with gene activation, direct evidence for its causal role in transcription, through specific MLL family members, is scarce. Here we have purified a human MLL2 (Kmt2b) complex that is highly active in H3K4 methylation and chromatin transcription in a cell-free system. This effect requires SAM and intact H3K4, establishing a direct and causal role for MLL2-mediated H3K4 methylation in transcription. We then show that human AKAP95, a chromatin-associated protein, is physically and functionally associated with the Dpy-30-MLL complexes and directly enhances their methyltransferase activity. Ectopic AKAP95 stimulates expression of a chromosomal reporter in synergy with MLL1 or MLL2, whereas AKAP95 depletion impairs retinoic acid-mediated gene induction in embryonic stem cells. These results demonstrate an important role for AKAP95 in regulating histone methylation and gene expression, particularly during cell fate transitions.

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RNA sequencing expression analysis of murine Tet-off MLL-AF9;NRAS acute myeloid leukemia cells over-expressing Id2 and upon MLL-AF9 withdrawal

Project description:We investigated the role of the transcriptional regulator Id2 in the context of MLL-rearranged acute myeloid leukemia (AML). Using an AML mouse model driven by tet-regulated MLL-AF9 co-expressed with oncogenic NRASG12D (Tet-off MLL-AF9), we demonstrated that MLL-AF9 regulates the E protein pathway by suppressing Id2, while activating the expression of its target E2-2. Moreover, we found that Id2 over-expression in Tet-Off MLL-AF9 AML cells in vitro partially phenocopies MLL-AF9 depletion and results inhibition of leukemia growth, loss of leukemia stem cell-associated gene expression pattern and induction of differentiation. To compare gene expression changes associated with enforced Id2 expression and MLL-AF9 withdrawal, RNA sequencing analysis was performed on Tet-off MLL-AF9 cells transduced with an Id2 over-expressing or a control vector, or upon MLL-AF9 dox-inducible knock-down.

2016-06-29 | GSE68462 | GEO

Regulation of transcription by MLL2 complex and MLL complexes-associated protein AKAP95

2013-07-01 | E-GEOD-48128 | biostudies-arrayexpress

Proteolytic cleavage by taspase1 and the regulation of the stability of MLL1

Project description:Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL-chimeras that drive pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase, taspase1, however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of full-length MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version and this stabilization of the uncleaved MLL1 can result in the displacement of MLL-chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL-chimeras from chromatin. Furthermore, inhibition of CKII in MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive MLL leukemia.

2019-01-02 | GSE90762 | GEO

RNA-seq profiling of murine Tet-off MLL-AF9; NRAS acute myeloid leukemia at different timepoints upon doxycycline-induced MLL-AF9 down-regulation.

Project description:Using an acute myeloid leukemia (AML) mouse model driven by tet-regulated MLL-AF9 (fusion between the gene MLL1 (KMT2A/MLL) and MLLT3 (AF9)) co-expressed with oncogenic NRASG12D (Tet-off MLL-AF9), we investigated the effect of modulating the expression of the MLL-AF9 fusion oncogene on the transcriptome and proteome of established murine AML. Treatment in vitro or in vivo of these Tet-off MLL-AF9 AMLs with doxycycline (DOX) results in the efficient down-regulation of the expression of the driver oncogene MLL-AF9. RNA sequencing analysis was performed on primary Tet-Off MLL-AF9 AML cells obtained from the spleen of leukemic animals and cultured in vitro for either 2 or 4 days in the presence of doxycycline (1μg/ml) (DOX= down-regulation of MLL-AF9) or left untreated (UT).

2021-12-31 | GSE108326 | GEO

Histone H3K36me2-specific methyltransferase ASH1L promotes the MLL-AF9-induced leukemogenesis

Project description:ASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in Ash1L gene knockout animal models. In this study, we used an Ash1L conditional knockout mouse model to show that loss of ASH1L in hematopoietic progenitor cells impaired the initiation of MLL-AF9-induced leukemic transformation in vitro. Furthermore, genetic deletion of ASH1L in the MLL-AF9-transformed cells impaired the maintenance of leukemic cells in vitro and largely blocked the leukemia progression in vivo. Importantly, the loss of ASH1L function in the Ash1L-deleted cells could be rescued by wild-type but not the catalytic-dead mutant ASH1L, suggesting the enzymatic activity of ASH1L was required for its function in promoting MLL-AF9-induced leukemic transformation. At the molecular level, ASH1L enhanced the MLL-AF9 target gene expression by directly binding to the gene promoters and modifying the local histone H3K36me2 levels. Thus, our study revealed the critical functions of ASH1L in promoting the MLL-AF9-induced leukemogenesis, which provides a molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-arranged leukemias.

2021-09-07 | GSE183413 | GEO

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