MLL-AF9– and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C

Zhu, Nan; Chen, Mo; Eng, Rowena; DeJong, Joshua; Sinha, Amit; Rahnamay, Noushin F.; Koche, Richard P.; Al‐Shahrour, Fátima; Minehart, Janna; Chen, Chun-Wei; Deshpande, Aniruddha J.; Xu, Haiming; Chu, S. Haihua; Ebert, Benjamin L.; Roeder, Robert G.; Armstrong, Scott A.

doi:10.1172/jci82978

Cited by 70 publications

(85 citation statements)

References 70 publications

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“…52 JMJD1C had also been recently implicated in AML1-ETO- 53 and HOXA9-mediated leukaemias. 54 JMJD1C was identified as a coactivator in AETFC, a complex formed by AML1-ETO, where JMJD1C maintained low level of H3K9me2, hence enhancing gene expression of AML1-ETO targets. Knockdown of JMJD1C compromised the ability of AML1-ETO to inhibit cell differentiation and impaired colony formation.…”

Section: The Role Of Hdms In Amlmentioning

confidence: 99%

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Epigenetic therapies by targeting aberrant histone methylome in AML: molecular mechanisms, current preclinical and clinical development

Tsai

2016

Oncogene

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While the current epigenetic drug development is still largely restricted to target DNA methylome, emerging evidence indicates that histone methylome is indeed another major epigenetic determinant for gene expression and frequently deregulated in acute myeloid leukaemia (AML). The recent advances in dissecting the molecular regulation and targeting histone methylome in AML together with the success in developing lead compounds specific to key histone methylation-modifying enzymes have revealed new opportunities for effective leukaemia treatment. In this article, we will review the emerging functions of histone methyltransferases and histone demethylases in AML, especially MLL-rearranged leukaemia. We will also examine recent preclinical and clinical studies that show significant promises of targeting these histone methylation-modifying enzymes for AML treatment.

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Section: The Role Of Hdms In Amlmentioning

confidence: 99%

“…Loss of JMJD1C profoundly affected leukaemic transformation driven by HOXA9, indicating yet another KDM family member with a more generic function in AML pathogenesis. 54 …”

Section: The Role Of Hdms In Amlmentioning

confidence: 99%

Epigenetic therapies by targeting aberrant histone methylome in AML: molecular mechanisms, current preclinical and clinical development

Tsai

2016

Oncogene

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“…Histone H3 lysine 9 (H3K9) demethylase JMJD1C is one of the most promising MLL r AL targets. Two independent studies, one analyzing 319 chromatin‐associated proteins and another examining 149 MLL‐AF9 targets, identified JMJD1C as being required for the development of MLL r AML but not for normal hematopoiesis . Additionally, JMJD1C was also reported to be a necessary element in the pathogenesis of AML1/ETO AML .…”

Section: Introductionmentioning

confidence: 99%

Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells

Wang

et al. 2019

Intl Journal of Cancer

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Histone demethylases are promising therapeutic targets as they play fundamental roles for survival of Mixed lineage leukemia rearranged acute leukemia (MLLr AL). Here we focused on the catalytic Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening. JMJD1C Jumonji domain inhibitor 4 (JDI‐4) and JDI‐12 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI‐4 and JDI‐12 bind to JMJD1C and its family homolog KDM3B with modest affinity. In vitro demethylation assays showed that JDI‐4 can reverse the H3K9 demethylation conferred by KDM3B. In vivo demethylation assays indicated that JDI‐4 and JDI‐12 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI‐4 and JDI‐12 kill MLLr AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI‐16, among multiple compounds structurally akin to JDI‐4/JDI‐12, exhibits superior killing activities against malignant hematopoietic cells compared to JDI‐4/JDI‐12. Mechanistically, JDI‐16 not only induces apoptosis but also differentiation of MLLr AL cells. RNA sequencing and quantitative PCR showed that JDI‐16 induced gene expression associated with cell metabolism; targeted metabolomics revealed that JDI‐16 downregulates lactic acids, NADP+ and other metabolites. Moreover, JDI‐16 collaborates with all‐trans retinoic acid to repress MLLr AML cells. In summary, we identified bona fide JMJD1C inhibitors that induce preferential death of MLLr AL cells.

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“…In this context, KDM3C directly interacts with HOXA9 and modulates a HOXA9-controlled gene expression program. Depletion of KDM3C in mice reduces the frequency of leukemia stem cells and causes differentiation of MLL-AF9-and HOXA9-driven leukemias [124]. In addition to its roles in leukemias, KDM3C levels are decreased in breast tumors, where it specifically coactivates androgen receptor and responds to alterations in systemic androgen levels [125].…”

Section: The Kdm3 Cluster (Jmjd1 Subfamily)mentioning

confidence: 99%

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

Verde

Querol-Paños²,

Cebrià-Costa³

et al. 2017

Epigenomes

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Histone modifications regulate chromatin structure, gene transcription, and other nuclear processes. Among the histone modifications, methylation has been considered to be a stable, irreversible process due to the slow turnover of methyl groups in chromatin. However, the discovery of three different classes of lysine-specific demethylases-KDM1, Jumonji domain-containing demethylases, and lysyl oxidase-like 2 protein-has drastically changed this view, suggesting a role for dynamic histone methylation in different biological process. In this review, we describe the different mechanisms that these enzymes use to remove lysine histone methylation and discuss their role during physiological (cell differentiation) and pathological (carcinogenesis) processes.

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MLL-AF9– and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C

Cited by 70 publications

References 70 publications

Epigenetic therapies by targeting aberrant histone methylome in AML: molecular mechanisms, current preclinical and clinical development

Epigenetic therapies by targeting aberrant histone methylome in AML: molecular mechanisms, current preclinical and clinical development

Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

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