Favorable outcomes of NPM1mut AML patients are due to transcriptional inactivation of FOXM1, presenting a new target to overcome chemoresistance
Year: 2023
Type: article
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 ].
Source: Blood Cancer Journal
Authors: I. Khan, A. Kaempf, S. Raghuwanshi, M. Chesnokov, X. Zhang, Z. Wang, A. Domling, J. W. Tyner, C. Camacho, A. L. Gartel
Institutions: Northwestern University, University of Illinois Chicago, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Oregon Health & Science University, OHSU Knight Cancer Institute, Spanish National Cancer Research Centre, University of Groningen, Palacký University Olomouc, University of Pittsburgh
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,790
Funders: Oregon Health and Science University, Northwestern University, University of Pittsburgh, Rijksuniversiteit Groningen, Univerzita Palackého v Olomouci, National Institutes of Health, University of Illinois at Urbana-Champaign, Knight Cancer Institute, Oregon Health and Science University, National Cancer Institute, National Center for Advancing Translational Sciences
OpenAlex ID: W4386048994