Favorable outcomes of NPM1mut AML patients are due to transcriptional inactivation of FOXM1, presenting a new target to overcome chemoresistance
Irum Khan, Andy Kaempf, Sanjeev Raghuwanshi, Mikhail S. Chesnokov, X. Zhang, Zhonghua Wang, Alexander Dömlingꝉ, Jeffrey Tyner, Carlos J. Camacho, Andrei L. Gartel
Abstract
Acute Myeloid Leukemia (AML) is a highly heterogeneous disease with 3-year patient survival ranging from 30 to 80%, depending on molecular characteristics. Mutations in nucleophosmin (NPM1 mut ), identified in a fourth of AML cases, are highly deterministic of treatment response [ 1 ]. The paradigm that clinically relevant NPM1 mutations aberrantly relocalize the NPM protein to the cytoplasm, producing favorable clinical outcomes, was first reported in 2005 . The NPM1 mutation confers superior responses to induction chemotherapy, as confirmed by multiple cooperative groups, and favorable responses to the BCL2 inhibitor, venetoclax [ 2 ]. However, the mechanistic basis for this treatment sensitization remains obscure. Our lab previously identified NPM1 as a binding partner of forkhead box M1 (FOXM1) and a critical determinant of FOXM1 cellular localization by performing reciprocal pull-down experiments, mass spectrometry, and confocal imaging on cell lines [ 3 ] and patient samples [ 4 ]. FOXM1 is a Forkhead family transcription factor that has been implicated in all the hallmarks of cancer. PRECOG meta-analysis identified the FOXM1 regulatory network as a major predictor of adverse outcomes across 30 tumor histologies [ 5 ]. We have previously demonstrated that knockdown of FOXM1 in AML cells and animal models of leukemia modulates sensitivity to chemotherapy and bcl2 inhibitors [ 6 , 7 ].