title: FOXM1 Transcription Factor: A New Component of Chronic Myeloid Leukemia Stem Cell Proliferation Advantage.
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.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Manuela
authors.identifier: 0000-0002-2972-5609
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Castagnetti
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Leo
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: De Benedittis
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gugliotta
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Rosti
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Bavaro
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: De Santis
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Monaldi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Martelli
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Santucci
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cavo
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Institute of Hematology L. and A. Seràgnoli-University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D049109:Cell Proliferation; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D009363:Neoplasm Proteins
keywords: BCR-ABL1; CHRONIC MYELOID LEUKEMIA; FOXM1; LEUKEMIC STEM CELSS; POLO-LIKE KINASE 1; TYROSINE KINASE INHIBITOR RESISTANCE