title: BCR-ABL1-associated reduction of beta catenin antagonist Chibby1 in chronic myeloid leukemia.
abstract: Beta Catenin signaling is critical for the self-renewal of leukemic stem cells in chronic myeloid leukemia. It is driven by multiple events, enhancing beta catenin stability and promoting its transcriptional co-activating function. We investigated the impact of BCR-ABL1 on Chibby1, a beta catenin antagonist involved in cell differentiation and transformation. Relative proximity of the Chibby1 encoding gene (C22orf2) on chromosome 22q12 to the BCR breakpoint (22q11) lets assume its involvement in beta catenin activation in chronic myeloid leukemia as a consequence of deletions of distal BCR sequences encompassing one C22orf2 allele. Forty patients with chronic myeloid leukemia in chronic phase were analyzed for C22orf2 relocation and Chibby1 expression. Fluorescent in situ hybridization analyses established that the entire C22orf2 follows BCR regardless of chromosomes involved in the translocation. In differentiated hematopoietic progenitors (bone marrow mononuclear cell fractions) of 30/40 patients, the expression of Chibby1 protein was reduced below 50% of the reference value (peripheral blood mononuclear cell fractions of healthy persons). In such cell context, Chibby1 protein reduction is not dependent on C22orf2 transcriptional downmodulation; however, it is strictly dependent upon BCR-ABL1 expression because it was not observed at the moment of major molecular response under tyrosine kinase inhibitor therapy. Moreover, it was not correlated with the disease prognosis or response to therapy. Most importantly, a remarkable Chibby1 reduction was apparent in a putative BCR-ABL1+ leukemic stem cell compartment identified by a CD34+ phenotype compared to more differentiated hematopoietic progenitors. In CD34+ cells, Chibby1 reduction arises from transcriptional events and is driven by C22orf2 promoter hypermethylation. These results advance low Chibby1 expression associated with BCR-ABL1 as a component of beta catenin signaling in leukemic stem cells.
authors: Istituto di Ematologia "Lorenzo e Ariosto Seràgnoli", Dipartimento di Medicina Specialistica Diagnostica e Sperimentale - DIMES, University of Bologna - Medical School, Bologna, Italy.
authors: Elisa
authors: E
authors: Leo
authors: Manuela
authors: M
authors: Mancini
authors: Michela
authors: M
authors: Aluigi
authors: Simona
authors: S
authors: Luatti
authors: Fausto
authors: F
authors: Castagnetti
authors: Nicoletta
authors: N
authors: Testoni
authors: Simona
authors: S
authors: Soverini
authors: Maria Alessandra
authors: MA
authors: Santucci
authors: Giovanni
authors: G
authors: Martinelli
mesh_terms: D021581:Active Transport, Cell Nucleus; D018952:Antigens, CD34 / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008958:Models, Molecular; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D015398:Signal Transduction; D015533:Transcriptional Activation; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; C473750:CBY1 protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D051176:beta Catenin; D016044:Fusion Proteins, bcr-abl