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

Abstract

In this report, we show that expression of a NUP98-PHF23 (NP23) fusion, associated with acute myeloid leukemia (AML) in humans, leads to myeloid, erythroid, T-cell, and B-cell leukemia in mice. The leukemic and pre-leukemic tissues display a stem cell-like expression signature including Hoxa, Hoxb, and Meis1 genes. The PHF23 PHD domain is known to bind H3K4me3 residues, and chromatin immunoprecipitation experiments demonstrated that the NP23 protein bound chromatin at a specific subset of H3K4me3 sites, including Hoxa, Hoxb, and Meis1. Treatment of NP23 cells with disulfiram, which inhibits the binding of PHD domains to H3K4me3 residues, rapidly and selectively killed NP23 myeloblasts; cell death was preceded by decreased expression of Hoxa, Hoxb, and Meis1. Furthermore, AML driven by a related fusion gene, NUP98-JARID1A (NJL), was also sensitive to disulfiram. Thus, the NP23 mouse provides a platform to evaluate compounds that disrupt binding of oncogenic PHD proteins to H3K4me3.

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

“…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.…”

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

“…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.…”

JARID1 Histone Demethylases: Emerging Targets in Cancer

“…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].…”