Description:

The Department of Biochemistry and Molecular Genetics welcomes you to attend a seminar by faculty candidate, Nicole Michmerhuizen, PhD, Postdoctoral Research Fellow, Pathology Department, St. Jude Children’s Research Hospital, Memphis, TN.

Seminar: "MOZ is a Critical Interacting Protein and Therapeutic Target in NUP98-Rearranged Acute Myeloid Leukemia"

Abstract: NUP98 fusion oncoproteins (FOs) have been reported in ~5% of pediatric acute myeloid leukemias (AMLs).  NUP98 fusions involve the N-terminal, intrinsically disordered region of NUP98 and the C-terminal portion of one of >30 identified fusion partners. Approximately one-third of partner genes have DNA-binding homeodomains, and most others have domains involved in gene regulation. Outcomes in children with NUP98-rearranged (NUP98-r) AML are poor, with relapse rates of nearly 70%. We recently reported that NUP98 FOs drive high-risk pediatric leukemias through mechanisms including liquid-liquid phase separation. Although we demonstrated the importance of phase separation in NUP98-r leukemic transformation, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. To identify FO interacting proteins, we performed rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) for wildtype NUP98 and eight NUP98 FOs (NUP98::HOXA9, PMX1, KDM5A, NSD1, JADE2, LNP1, RAP1GDS1, SETBP1) in transfected HEK293T cells. In addition to known NUP98 FO interactors (e.g. XPO1, RAE1), we identified novel interactors including MOZ and other histone acetyltransferase (HAT) complex members.  Further, in vivo CRISPR/Cas9 screening with a library of epigenetic gRNAs suggested that BRPF1, an epigenetic writer that associates with MOZ and other HAT complexes, is a molecular dependency in NUP98::KDM5A AML. Competitive co-culture of Nup98::Kdm5a;Vav-Cre cells showed that inactivation of Brpf1 as well as Moz, Hbo1, Brd1 or Meaf6 decreased NUP98-r cell fitness. Furthermore, MOZ inhibition decreased proliferation of NUP98-r cells and was synergistic in combination with Menin inhibitor treatment. MOZ and Menin inhibition displaced FO from chromatin at FO target genes, led to myeloid cell differentiation, and showed efficacy in patient-derived xenografts. In summary, our studies show that MOZ is a potentially targetable dependency in NUP98-rearranged AMLs.