MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia

Riedel, Simone S.; Haladyna, Jessica N.; Bezzant, Matthew; Stevens, Brett M.; Pollyea, Daniel A.; Sinha, Amit; Armstrong, Scott A.; Wei, Qi; Pollock, Roy M.; Daigle, Scott R.; Jordan, Craig T.; Ernst, Patricia; Neff, Tobias; Bernt, Kathrin M.

doi:10.1172/jci80825

Cited by 36 publications

(35 citation statements)

References 41 publications

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“…To discover and identify potential molecules and signaling pathways involved in the growth of melanoma, we screened a siRNA library targeting >6000 human genes in A375 melanoma cells and found that KMT2A knockdown by siRNA significantly suppressed the cell viability by 76.0% ( Figure 1a ), indicating that KMT2A, a transcriptional co-activator in cancer, 15 , 46 , 47 could be a melanoma target.…”

Section: Resultsmentioning

confidence: 99%

KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway

et al. 2017

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Melanoma is an aggressive cutaneous malignancy, illuminating the exact mechanisms and finding novel therapeutic targets are urgently needed. In this study, we identified KMT2A as a potential target, which promoted the growth of human melanoma cells. KMT2A knockdown significantly inhibited cell viability and cell migration and induced apoptosis, whereas KMT2A overexpression effectively promoted cell proliferation in various melanoma cell lines. Further study showed that KMT2A regulated melanoma cell growth by targeting the hTERT-dependent signal pathway. Knockdown of KMT2A markedly inhibited the promoter activity and expression of hTERT, and hTERT overexpression rescued the viability inhibition caused by KMT2A knockdown. Moreover, KMT2A knockdown suppressed tumorsphere formation and the expression of cancer stem cell markers, which was also reversed by hTERT overexpression. In addition, the results from a xenograft mouse model confirmed that KMT2A promoted melanoma growth via hTERT signaling. Finally, analyses of clinical samples demonstrated that the expression of KMT2A and hTERT were positively correlated in melanoma tumor tissues, and KMT2A high expression predicted poor prognosis in melanoma patients. Collectively, our results indicate that KMT2A promotes melanoma growth by activating the hTERT signaling, suggesting that the KMT2A/hTERT signaling pathway may be a potential therapeutic target for melanoma.

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Section: Resultsmentioning

confidence: 99%

KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway

et al. 2017

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“…Differentiation, proliferation, survival, self-renewal in vitro and in vivo, as well as the maintenance of leukemogenic MLL-FP direct target gene expression were all unaffected by deletion of endogenous Mll1 using two distinct conditional knockout models and human leukemia cells. Importantly, loss of Mll1 alone can have a major impact in other AML models, including those initiated by MN1 and Nup98 fusion proteins (Riedel et al, 2016; Xu et al, 2016). In searching for an explanation for our results, we uncovered a role for the MLL1 paralog, MLL2, which had not previously been implicated in leukemia.…”

Section: Discussionmentioning

confidence: 99%

MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia

et al. 2017

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Summary 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.

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“…Recently, deletion of the endogenous Mll1 gene in NUP98-HOXA9 or MN1-driven acute myelogenous leukemia (AML) demonstrated that endogenous MLL1 activity does contribute to leukemia maintenance in each of these distinct cytogenetic AML models [35**,36]. The role of endogenous MLL1 in MLL-driven leukemia is evolving, with some studies suggesting that it is required and some suggesting that it is not [27,37–39].…”

Section: Mll1 and Mll2mentioning

confidence: 99%

Distinct functions of histone H3, lysine 4 methyltransferases in normal and malignant hematopoiesis

Yang

Ernst

2017

Current Opinion in Hematology

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Purpose of review Histone H3, lysine 4 methylation (H3K4me) is one chromatin modification that defines distinct regulatory states of euchromatin. Mammals express 6 main histone methyltransferase enzymes (HMTs) that modify H3K4 by mono-, di-, or tri-methylation. Recent studies examine roles of some of these HMTs and their cofactors in hematopoiesis and leukemia. We discuss these emerging studies together with prior embryonic stem (ES) data revealing how these enzymes function. Recent findings Murine models have been employed to conditionally or constitutively knock out HMTs (MLL1/KMT2A, MLL2/KMT2B, MLL3/KMT2C, MLL4/KMT2D, SETD1A/KMT2F and SETD1B/KMT2G) as well as specific domains or partners of these enzymes in normal hematopoietic populations and in the context of hematologic malignancies. These studies demonstrate that global or gene-specific changes in H3K4 modification levels can be attributed to particular enzymes in particular tissues. Summary Loss-of-function studies indicate largely non-overlapping roles of the six H3K4 HMTs. These roles are not all necessarily due to differences in enzymatic activity and are not always accompanied by large global changes in histone modification. Both gain- and loss-of-function mutations in hematologic malignancy are restricted to MLL1 and MLL3/MLL4, but emerging data indicate that SETD1A/SETD1B and MLL2 can be critical in leukemia as well.

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MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia

Cited by 36 publications

References 41 publications

KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway

KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway

MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia

Distinct functions of histone H3, lysine 4 methyltransferases in normal and malignant hematopoiesis

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