FOXM1 Transcription Factor: A New Component of Chronic Myeloid Leukemia Stem Cell Proliferation Advantage. Issue 11 (30th May 2017)

• Record Type: Journal Article
• Authors: Mancini, Manuela; Castagnetti, Fausto; Soverini, Simona; Leo, Elisa; De Benedittis, Caterina; Gugliotta, Gabriele; Rosti, Gianantonio; Bavaro, Luana; De Santis, Sara; Monaldi, Cecilia; Martelli, Margherita; Santucci, Maria Alessandra; Cavo, Michele; Martinelli, Giovanni
• Is Part Of: Journal of cellular biochemistry. Volume 118:Issue 11(2017)
• Page Start: 3968
• Page End: 3975
• Publication Date: 2017-05-30
• Subjects: CHRONIC MYELOID LEUKEMIA -- BCR‐ABL1 -- LEUKEMIC STEM CELSS -- FOXM1 -- POLO‐LIKE KINASE 1 -- TYROSINE KINASE INHIBITOR RESISTANCE; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.26052
• Languages: English
• ISSNs: 0730-2312

Abstract

ABSTRACT: FOXM1 transcription factor is a central component of tumor initiation, growth, and progression due to its multiple effects on cell cycle, DNA repair, angiogenesis and invasion, chromatin, protein anabolism, and cell adhesion. Moreover, FOXM1 interacts with β‐catenin promoting its nuclear import and transcriptional activation. Here, we show that FOXM1 is involved in the advantage of chronic myeloid leukemia hematopoiesis over the normal counterpart. FOXM1 hyper‐activation associated with BCR‐ABL1 results from phosphorylation by the fusion protein kinase‐dependent activation of Polo‐like kinase 1. FOXM1 phosphorylation lets its binding with β‐catenin and β‐catenin transcriptional activation, a key event for persistence of the leukemic stem cell compartment under tyrosine kinase inhibitor therapy. Polo‐like kinase 1 inhibitor BI6727, already advanced for clinical use, breaks β‐catenin interaction with FOXM1, hence hampering FOXM1 phosphorylation, β‐catenin binding, nuclear import, and downstream signaling. In conclusion, our results support Polo‐like kinase 1/FOXM1 axis as a complementary target to eradicate leukemic early progenitor/stem cell compartment in chronic myeloid leukemia. J. Cell. Biochem. 118: 3968–3975, 2017. © 2017 Wiley Periodicals, Inc. Abstract : FOXM1 overexpression and hyper‐activation associated with BCR‐ABL1 are components of proliferative advantage and drug resistance of leukemic cells. FOXM1 hyper‐activation is induced by Polo‐like kinase constitutively activated by BCR‐ABL1 tyrosine kinase. FOXM1 impact on the BCR‐ABL1‐transformed phenotype is driven by its binding with beta‐catenin, which lets beta‐catenin nuclear import and transcriptional activation. FOXM1 overexpression in BCR‐ABL1+ stem cells, characterized by CD34+ phenotype, may contribute to their persistence under tyrosine kinase inhibitor therapy. FOXM1/Polo‐like kinase 1 may be therefore advanced as complementary targets to eradicate the disease.