FOXM1 Transcription Factor Is a Component of Beta Catenin Signaling in Hematopoietic Progenitors of Chronic Myeloid Leukemia
Authors: Leo Elisa , Simonetti Giorgia , Mancini Manuela , Veljkovic Nevena , Campi Virginia , Castagnetti Fausto , Gugliotta Gabriele , De Benedittis Caterina , Santucci Maria Alessandra , Martinelli Giovanni 
Published: November 2019

FOXM1 is a transcription factor of the Forkhead family which drives beta catenin nuclear import and transcriptional activation.Notably, it is a central component of a network which lets tumor cells bypass replicative stress and senescence and maintains the stem cell pluripotency. Accordingly, FOXM1 may have a role in the proliferative advantage and genomic instability of clonal hematopoiesis and leukemic stem cells (LSCs) of chronic myeloid leukemia (CML).Multiple events, including inactivation of protein phosphatase 2A (PP2A, which antagonizes cyclin A/Cdk-dependent activation of FOXM1), activation of Polo-like kinase 1 (PLK1, which directly promotes FOXM1 activating phosphorylation), suppression of Raf kinase inhibitor protein (RKIP, which down-regulates FOXM1 expression), depletion of APC/CDH1 E3 ligase (which degrades FOXM1 at mitotic exit) and down-regulation of micro RNA 370 (miR-370, which directly targets FOXM1 3’ UTR) may concur to BCR-ABL1-associated activation of FOXM1.

Experiments carried in BCR-ABL1+ cell lines (K562 and 32D cell clones transduced with a temperature-sensitive mutant of BCR-ABL1 let establish that: 1-FOXM1 activation associated with BCR-ABL1 tyrosine kinase (TK) proceeds from post-transcriptional events encompassing the protein phosphorylation at serine-threonine residues and driving PLK1 activating phosphorylation; 2-FOXM1 phosphorylation is a key event for the interaction with beta catenin and PLK1; 3- the PLK1 inhibitor BI-2536, besides reducing the interaction of FOXM1 protein with beta catenin through events encompassing PLK1-induced phosphorylation of FOXM1, results in a significant reduction of FOXM1 transcript, suggesting a feedback mechanism involved in the regulation of FOXM1 expression in a BCR-ABL1+ cell context. Notably, a significant increment of FOXM1 transcript was found in mononuclear cells from bone marrow samples of 9 out of 15 CML patients at diagnosis compared to hematological healthy donors, which returned to control values in 4/4 patients when they reached a major molecular response to therapy with TK inhibitors. Computational analysis of FOXM1 sequences let distinguish the region encompassing a.a. 561-645 (ARM 10-12) as the one involved in FOXM1 interaction with a.a. 561-645 (ARM 10-12) of beta catenin. Site-directed mutagenesis of above mentioned FOXM1 and beta catenin regions (in progress) would let define FOXM1 role in the transformed phenotype associated with BCR-ABL1 and proceeding from FOXM1-mediated activation of beta catenin. The identification of FOXM1 as a component of BCR-ABL1-induced transformation may help in designing therapeutic strategies to specifically target beta catenin in clonal progenitors and LSCs, sparing the beta catenin signaling in other cell types, particularly, in normal hematopoietic stem cells.

Acknowledgments: Umberto Veronesi Foundation, ELN, BolognaAIL, AIRC, PRIN, progetto Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project are acknowledged for financial support. MM is the recipient of a grant provided by the Umberto Veronesi Foundation.

Disclosures

Castagnetti: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy. Gugliotta:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy.