JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis

Lynch, Jodi; Salik, Basit; Connerty, Patrick; Vick, Binje; Leung, Halina; Pijning, Aster E.; Jeremias, Irmela; Spiekermann, Karsten; Trahair, Toby N.; Liu, Tao; Haber, Michelle; Norris, Murray D.; Woo, Andrew; Hogg, Philip J.; Wang, Jianlong; Wang, Jenny

doi:10.1038/s41375-018-0354-z

Cited by 33 publications

(38 citation statements)

References 42 publications

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“…A very recent paper by Lynch et al . showed that JMJD1C upregulates cell metabolism‐associated genes including ALDOC, PGK1, PKM2 and LDHA that have been confirmed by Western blot, ALDOA, PGAM1, PFKP, TPI1, ENO1, IDH2 and VEGFA that have been shown by microarray . These mice leukemia stem cells‐based results are stupendously consistent with our cell lines‐based data that showed metabolism‐associated genes are regulated by JDI‐16 in MLLr AL cells but not AML1‐ETO AML cells (Fig.…”

Section: Discussionsupporting

confidence: 89%

“…In support of this, a very recent paper showed that JMJD1C upregulates metabolism‐associated genes including LDHA, increases rates of glycolysis and mitochondrial oxidative phosphorylation (OXPHOs) for ATP generation, and protects leukemic cells from high glucose‐induced repression of OXPHOS. JMJD1C may affect leukemogenesis by influencing cell metabolism programs …”

Section: Introductionmentioning

confidence: 99%

“…JMJD1C may affect leukemogenesis by influencing cell metabolism programs. 8 Furthermore, JMJD1C has been shown to play a fundamental role in distinct cell metabolism pathways. The genetic polymorphisms of JMJD1C have been found to be associated with the plasma concentration of various lipids, 9 especially triglycerides (TG) 10,11 and n − 6 polyunsaturated fatty acids (PUFAs), 12 as well as the serum androgen levels, 13 revealed by a genome-wide association study by multiple independent research groups.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells

Wang

et al. 2019

Intl Journal of Cancer

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“…Although a few regulators of HOXA9 in MLLr leukemia have been previously identified (9, 11, 33–39), to date a comprehensive CRISPR/Cas9 screen to unbiasedly identify novel upstream regulatory factors of HOXA9 has not been feasible owing to the lack of a reliable reporter cell line. Therefore, we combined the HOXA9 P2A-mCherry reporter line and an in-house CRISPR-Cas9 sgRNA library targeting 1,639 human transcription factors to identify novel regulatory effectors (40).…”

Section: Resultsmentioning

confidence: 99%

Functional Interrogation of HOXA9 Regulome in MLLr Leukemia via Reporter-based CRISPR/Cas9 screen

Zhang

Wright

et al. 2020

Preprint

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Aberrant HOXA9 expression is a hallmark of most aggressive acute leukemias, including human acute myeloid leukemia (AML) and subtypes of acute lymphoblastic leukemia (ALL). HOXA9 overexpression not only predicts poor diagnosis and outcome but also plays a critical role in leukemia transformation and maintenance. However, our current understanding of HOXA9 regulation in leukemia is limited, hindering development of therapeutic strategies to treat HOXA9-driven leukemia. To mitigate these challenges, we generated the first HOXA9-mCherry knock-in reporter in an MLL-rearranged (MLLr) B-ALL cell line to dissect HOXA9 regulation. By utilizing the reporter and CRISPR/Cas9 mediated screens, we identified transcription factors controlling HOXA9 expression, including a novel regulator, USF2 and its homolog USF1. USF1/USF2 depletion significantly down-regulated HOXA9 expression and impaired MLLr leukemia cell proliferation. Ectopic expression of HOXA9-MEIS1 fusion protein rescued the impaired leukemia cell proliferation upon USF2 loss. Cut&Run analysis revealed the direct occupancy of USF2 onto HOXA9 promoter in MLLr leukemia cells. Collectively, the HOXA9 reporter facilitated the functional interrogation of the HOXA9 regulome and has advanced our understanding of the molecular regulation network in HOXA9-driven leukemia.

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“…The results of the study in MDS patients revealed that KDM2B could indirectly reduce the expression of p16 via let7b/EZH2 pathway [25]. Several lines of evidence have also demonstrated that KDM3C is necessary for self-renewal of AML cells and could be applied as a potential target for anticancer therapy [26]. Regarding the paradoxical functions of SUV39H1 and KDM3C in catalyzing and erasing of H3K9me, it is interesting to evaluate the correlation of these genes with the expression of TSGs in AML patients.…”

Section: Introductionmentioning

confidence: 99%

Transcription Analysis of a Histones Modifiers Panel Coupled with Tumor Suppressor Genes Displayed Frequent Changes in Acute Myeloid Leukemia-Related Genes

Amiri

Mohammadi

Rafiee

et al. 2020

Preprint

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Introduction Epigenetic alterations could cause leukemia through the activation of normally silent loci or silencing of normally active loci. We herein aimed to compare the expression patterns of a histone modifiers panel consisted of SUV39H1, PRDM16, UHRF2, KDM2B, and KDM3C between acute myeloid leukemia(AML) cells and normal cells and to assess the correlation of these genes with the expression of vital tumor suppressor genes, including p16INK4A and p53.Materials and methods Bone marrow or peripheral blood samples of 50 AML patients at diagnosis and also 18 subjects with a normal hematopoietic system as a control group were obtained after informed consent. Then, qRT-PCR was performed to determine the expression levels of the aforementioned genes. Results We found a broad alteration in the expression signature of five out of seven studied genes in AML patients as compared with the control group. UHRF2 and p53 were remarkably downregulated in AML patients (P < 0.001), while SUV39H1, PRDM16, and KDM3C significantly overexpressed (P< 0.01). Based on the Spearman rank correlation, SUV39H1, KDM2B, and age of the patients negatively regulated both p16INK4A and p53 expression. Conclusion Taken together, our findings provided preliminary evidence regarding the pervasive mRNA perturbation of histone modifiers and their plausible influences on critical tumor suppressor genes. Future studies in this area would be required to assist in establishing these results in the clinical practice of AML patients.

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JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis

Cited by 33 publications

References 42 publications

Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells

Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells

Functional Interrogation of HOXA9 Regulome in MLLr Leukemia via Reporter-based CRISPR/Cas9 screen

Transcription Analysis of a Histones Modifiers Panel Coupled with Tumor Suppressor Genes Displayed Frequent Changes in Acute Myeloid Leukemia-Related Genes

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