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.
Highlights
The BCR-ABL1 fusion gene is the causative genetic lesion of chronic myeloid leukemia (CML) [1]
Fluorescent in situ hybridization (FISH) patterns of BCR/ABL1 and C22orf2 were investigated in mononuclear cell fractions (MCF) from bone marrow samples of CML-chronic phase (CP) patients
FISH pattern in MCF from HP peripheral blood consists of two green and red signals, marking ABL on chromosomes 9 and BCR on chromosomes 22, respectively (Figure S1, panel A) All CML-CP patients with typical t(9;22) translocation displayed one BCRABL1 fusion signal at the Ph1 chromosome (22q-), one green signal corresponding to normal BCR at 22q and one red signal corresponding to normal ABL at the 9q (Figure 1B-panel A)
Summary
The BCR-ABL1 fusion gene is the causative genetic lesion of chronic myeloid leukemia (CML) [1]. Beta Catenin is a central component of self-renewal of BCRABL1+ LSC and reprogramming of committed granulocyte/ macrophage progenitors (GMP) into LSC at the blast crisis (BC) onset [5,6,7] It is involved in microenvironmental protection of CML stem and progenitor cells from TK inhibitors [8]. Multiple events contribute to beta catenin stabilization in CML They encompass the BCR-ABL1-mediated beta catenin phosphorylation at specific tyrosine residues (Y86 and Y654), resulting in its impaired recruitment by the Axin/glycogen synthase kinase 3 beta (GSK3b) destruction complex, BCRABL1-associated overexpression of growth arrest specific 2 (GAS2), reducing its degradation by the calpaine system, and GSK3b inactivation due to the prevalence of a GSK3b mis-spliced isoform unable to phosphorylate beta catenin and/or to GSK3b de-phosphorylation by the Fas associated phosphatase 1 (Fap1) [9,10,11,12]. Beta catenin enters the nucleus to form a transcription complex with TCF/LEF factors and activates the expression of target genes, such as c-Myc and cyclin D1 [13]
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