NUP98–PHF23 Is a Chromatin-Modifying Oncoprotein That Causes a Wide Array of Leukemias Sensitive to Inhibition of PHD Histone Reader Function

Gough, Sheryl M.; Lee, Fan; Yang, Fan; Walker, Robert L.; Zhu, Yeulin J.; Pineda, Marbin; Onozawa, Masahiro; Chung, Yang Jo; Bilke, Sven; Wagner, Elise K.; Denu, John M.; Ning, Yi; Xu, Bowen; Wang, Gang Greg; Meltzer, Paul S.; Aplan, Peter D.

doi:10.1158/2159-8290.cd-13-0419

Cited by 73 publications

(94 citation statements)

References 49 publications

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“…The reason for this mutational pattern is most likely related to the choice of the initiating mutation, namely, the transgene. Expression of CALM‐AF10 or Nup98‐fusion proteins has been shown to induce expression of the HoxA gene cluster, leading to impaired differentiation . Therefore, acquisition of additional differentiation‐impairing mutations would likely provide little selective advantage, whereas mutations contributing to proliferation and survival are positively selected.…”

Section: Discussionmentioning

confidence: 99%

Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance

Goldberg

Gough

Lee

et al. 2017

Genes Chromosomes & Cancer

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Malignant transformation is a multistep process that is dictated by acquisition of multiple genomic aberrations that provide growth and survival advantage. During the post genomic era, high throughput genomic sequencing has advanced exponentially, leading to identification of countless cancer associated mutations with potential for targeted therapy. Mouse models of cancer serve as excellent tools to examine the functionality of gene mutations and their contribution to the malignant process. However, it remains unclear whether the genetic events that occur during transformation are similar in mice and humans. To address that, we chose several transgenic mouse models of hematopoietic malignancies and identified acquired mutations in these mice by means of targeted re-sequencing of known cancer-associated genes as well as whole exome sequencing. We found that mutations that are typically found in acute myeloid leukemia or T cell acute lymphoblastic leukemia patients are also common in mouse models of the respective disease. Moreover, we found that the most frequent mutations found in a mouse model of lymphoma occur in a set of epigenetic modifier genes, implicating this pathway in the generation of lymphoma. These results demonstrate that genetically engineered mouse models (GEMM) mimic the genetic evolution of human cancer and serve as excellent platforms for target discovery and validation.

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Section: Discussionmentioning

confidence: 99%

Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance

Goldberg

Gough

Lee

et al. 2017

Genes Chromosomes & Cancer

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“…All the NUP98 -translocations produce gene rearrangements that encode fusion proteins which possess a common NH 3 -terminus which invariably contains the FG/GLFG repeat motifs and GLEBS domain fused in-frame with various COOH-terminal fusion partners. Studies using mouse models expressing NUP98 fusions confirm their leukemogenic potential (Kroon et al, 2001; Pinearlt et al, 2003; Gurevich et al, 2004, Wang et al, 2007, Wang et al, 2009; Gough et al, 2014). However, the molecular mechanisms of NUP98 -fusion mediated leukemogenesis and elevated HOX gene expression in this leukemia are unclear.…”

Section: Introductionmentioning

confidence: 87%

NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis

et al. 2016

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Summary The Nucleoporin 98 gene (NUP98) is fused to a variety of partner genes in multiple hematopoietic malignancies. Here we demonstrate that NUP98 fusion proteins, including NUP98-HOXA9 (NHA9), NUP98-HOXD13 (NHD13), NUP98-NSD1, NUP98-PHF23, and NUP98-TOP1 physically interact with mixed lineage leukemia 1 (MLL1) and the non-specific lethal (NSL) histone-modifying complexes. ChIP-seq illustrates that NHA9 and MLL1 co-localize on chromatin and are found associated with Hox gene promoter regions. Furthermore, MLL1 is required for the proliferation of NHA9 cells in vitro and in vivo. Inactivation of MLL1 leads to decreased expression of genes bound by NHA9 and MLL1 and reverses a gene expression signature found in NUP98-rearranged human leukemias. Our data reveal a molecular dependency on MLL1 function in NUP98-fusion driven leukemogenesis.

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“…This limitation explains the lack of specificity of early inhibitors such as 2,4-PDCA [75], PBIT [76], and hydroxamate compounds [77]. A nonselective inhibitory mechanism based on the ability of disulfiram to inhibit JARID1A’s PHD3 binding to H3K4me3 has also been described and used to inhibit growth of AMLs driven by a NUP98-JARID1A fusion gene [78]. Recent structural analyses identifying amino acid side chains and conformational plasticity unique to the JARID1 active sites have facilitated improvements in potency and selectivity of inhibitors [79, 80].…”

Section: Targeting Jarid1 Functionmentioning

confidence: 99%

JARID1 Histone Demethylases: Emerging Targets in Cancer

et al. 2017

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JARID1 proteins are histone demethylases that both regulate normal cell fates during development and contribute to the epigenetic plasticity that underlies malignant transformation. This H3K4 demethylase family participates in multiple repressive transcriptional complexes at promoters and has broader regulatory effects on chromatin that remain ill-defined. There is growing understanding of the oncogenic and tumor suppressive functions of JARID1 proteins, which are contingent on cell context and the protein isoform. Their contributions to stem cell-like de-differentiation, tumor aggressiveness, and therapy resistance in cancer have sustained interest in the development of JARID1 inhibitors. Here we review the diverse and context-specific functions of the JARID1 proteins that may impact the utilization of emerging targeted inhibitors of this histone demethylase family in cancer therapy.

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NUP98–PHF23 Is a Chromatin-Modifying Oncoprotein That Causes a Wide Array of Leukemias Sensitive to Inhibition of PHD Histone Reader Function

Cited by 73 publications

References 49 publications

Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance

Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance

NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis

JARID1 Histone Demethylases: Emerging Targets in Cancer

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