Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities

Cardin, Sophie; Bilodeau, Mélanie; Roussy, Mathieu; Aubert, Laura; Milan, Thomas; Jouan, Loubna; Rouette, Alexandre; Laramée, Louise; Gendron, Patrick; Duchaine, Jean; Decaluwe, Hélène; Spinella, Jean-François; Mourad, Stephanie; Couture, Françoise; Sinnett, Daniel; Haddad, Élie; Landry, Josette‐Renée; Ma, Jing; Humphries, R. Keith; Roux, Philippe P.; Grüber, Tanja A.; Wilhelm, Brian T.; Cellot, Sonia

doi:10.1182/bloodadvances.2019030981

Cited by 23 publications

(35 citation statements)

References 50 publications

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“…Mechanistically, marked overexpression of Hoxa cluster genes, most notably Hoxa-5, -7, -9 , and -10 , is linked with leukemic characteristics [ 89 ]. NUP98/JARID1A is involved with promoting expression of the Hoxa gene cluster via specifically binding to their promoters, deregulating the “reader” of histone marks, resulting in the inhibition of the epigenetic program necessary for regular cell differentiation [ 14 ]. Furthermore, KDM5A mediates drug resistance to Wee1 inhibition in acute leukemia [ 91 ].…”

Section: Kdm5a In Human Cancermentioning

confidence: 99%

“…KDM5A can eliminate di- and tri-methyl moieties from the fourth lysine of histone 3 (H3K4me2/3), which leads to the activation or repression of transcription [ 3 – 13 ]. Additionally, the fusion gene NUP98-KDM5A, which is produced by rearrangement between NUP98 and KDM5A, mediates hematopoietic cell proliferation and alters myelo-erythropoietic differentiation via demethylating H3K4me2/3 [ 14 – 17 ]. In terms of mechanism, KDM5A and its fusion gene Fe(II)-dependently catalyzes oxidative decarboxylation of 2OG with consumption of O 2 to generate a reactive iron(IV)-oxo intermediate, carbon dioxide, and succinate.…”

Section: Introductionmentioning

confidence: 99%

“…Among the Fe(II)- and 2OG-dependent demethylases, KDM5A exhibits variable levels in the body [ 21 – 23 ]. However, KDM5A showed aberrantly high expression in various solid cancers as well as in acute myeloid leukemia (AML), where it represses differentiation, promotes angiogenesis, drug resistance, and epithelial-mesenchymal transition, enhances adhesion, metastasis, invasiveness, proliferation, and cell motility, and also worsens outcomes [ 5 , 6 , 8 – 10 , 14 , 21 – 29 ]. Therefore, inhibiting KDM5A is potentially an antitumor approach.…”

Section: Introductionmentioning

confidence: 99%

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The emerging role of KDM5A in human cancer

Yang

Zhu

et al. 2021

J Hematol Oncol

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Histone methylation is a key posttranslational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Variations in the pattern of histone methylation influence both physiological and pathological events. Lysine-specific demethylase 5A (KDM5A, also known as JARID1A or RBP2) is a KDM5 Jumonji histone demethylase subfamily member that erases di- and tri-methyl groups from lysine 4 of histone H3. Emerging studies indicate that KDM5A is responsible for driving multiple human diseases, particularly cancers. In this review, we summarize the roles of KDM5A in human cancers, survey the field of KDM5A inhibitors including their anticancer activity and modes of action, and the current challenges and potential opportunities of this field.

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Section: Kdm5a In Human Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The emerging role of KDM5A in human cancer

Yang

Zhu

et al. 2021

J Hematol Oncol

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“…A subset of AML cases shows abnormal chromosomal translocations that involve nucleoporin 98 (NUP98) and its fusion partners and components of the epigenetic machinery, such as KDM5A/ JARID1A, NSD1, NSD3, LEDGF, BPTF, and PHF23 [3][4][5][6][7][8][9] . The fused chimeras activate HOX gene-dependent oncogenic programs and induce leukemic transformation in mice and in human hematopoietic stem cells 4,[8][9][10] .…”

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confidence: 99%

Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion

et al. 2020

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Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and is inhibited by small molecule compounds, including disulfiram that directly targets the PHD finger of PHF23 (PHF23PHD). Our data support a critical role for the PHD fingers of NUP98-PHF23, and related NUP98-KDM5A and NUP98-BPTF fusions in driving leukemogenesis, and demonstrate that blocking this interaction in NUP98-PHF23 expressing AML cells leads to cell death through necrotic and late apoptosis pathways. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq, together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF, suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98 fusions. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3enriched chromatin and leukemic transformation.

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“…Thanks to gene expression profiling, distinct genomic profiles in Non-DS AMKL cohort cluster together: KMT2A-R, NUP98-KDM5A, HOX-R, CBFA2T3-GLIS2, GATA1 mutant ( Figure 2) [4]. KMT2A-R and NUP98-KDM5Asubtypes showed upregulation of HOX cluster genes, demonstrating that about 50% of pediatric non-DS-AMKL patients carry a HOX gene expression program [4,6,50]. Cryptic CBFA2T3-GLIS2 inversion cluster away from other non-DS-AMKL [4].…”

Section: Gene Expression Profilingmentioning

confidence: 99%

Infant Acute Myeloid Leukemia: A Unique Clinical and Biological Entity

Calvo

Fenneteau

Leverger³

et al. 2021

Cancers

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Infant acute myeloid leukemia (AML) is a rare subgroup of AML of children <2 years of age. It is as frequent as infant acute lymphoblastic leukemia (ALL) but not clearly distinguished by study groups. However, infant AML demonstrates peculiar clinical and biological characteristics, and its prognosis differs from AML in older children. Acute megakaryoblastic leukemia (AMKL) is very frequent in this age group and has raised growing interest. Thus, AMKL is a dominant topic in this review. Recent genomic sequencing has contributed to our understanding of infant AML. These data demonstrated striking features of infant AML: fusion genes are able to induce AML transformation without additional cooperation, and unlike AML in older age groups there is a paucity of associated mutations. Mice modeling of these fusions showed the essential role of ontogeny in the infant leukemia phenotype compared to older children and adults. Understanding leukemogenesis may help in developing new targeted treatments to improve outcomes that are often very poor in this age group. A specific diagnostic and therapeutic approach for this age group should be investigated.

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Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities

Abstract: Key PointsEngineered human models of high-fatality pediatric leukemia are relevant to uncover disease biomarkers and therapeutic vulnerabilities. NUP98-KDM5A–associated AMKL expresses SELP, MPIG6B, and NEO1 biomarkers and is sensitive to pharmacologic inhibition with ruxolitinib.

Cited by 23 publications

References 50 publications

The emerging role of KDM5A in human cancer

The emerging role of KDM5A in human cancer

Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion

Infant Acute Myeloid Leukemia: A Unique Clinical and Biological Entity

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