Embryonic Program Activated during Blast Crisis of Chronic Myelogenous Leukemia (CML) Implicates a TCF7L2 and MYC Cooperative Chromatin Binding.

Christophe Desterke,Annelise Bennaceur-Griscelli,Patricia Hugues,Ali G Turhan,Jin Wook Hwang

doi:10.3390/ijms21114057

Christophe Desterke, Annelise Bennaceur-Griscelli + Show 3 more

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https://doi.org/10.3390/ijms21114057

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Abstract

Chronic myeloid leukemia (CML) is characterized by an inherent genetic instability, which contributes to the progression of the disease towards an accelerated phase (AP) and blast crisis (BC). Several cytogenetic and genomic alterations have been reported in the progression towards BC, but the precise molecular mechanisms of this event are undetermined. Transcription Factor 7 like 2 (TFC7L2) is a member of the TCF family of proteins that are known to activate WNT target genes such as Cyclin D1. TCF7L2 has been shown to be overexpressed in acute myeloid leukemia (AML) and represents a druggable target. We report here that TCF7L2 transcription factor expression was found to be correlated to blast cell numbers during the progression of the disease. In these cells, TCF7L2 CHIP-sequencing highlighted distal cis active enhancer, such as elements in SMAD3, ATF5, and PRMT1 genomic regions and a proximal active transcriptional program of 144 genes. The analysis of CHIP-sequencing of MYC revealed a significant overlapping of TCF7L2 epigenetic program with MYC. The β-catenin activator lithium chloride and the MYC-MAX dimerization inhibitor 10058-F4 significantly modified the expression of three epigenetic targets in the BC cell line K562. These results suggest for the first time the cooperative role of TCF7L2 and MYC during CML-BC and they strengthen previous data showing a possible involvement of embryonic genes in this process.

Highlights

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell malignancy characterized by the presence of the chromosomal translocation t(9;22) generating Philadelphia (Ph1) chromosome in all leukemic cells [1]
Transcriptome experiments performed on CD34+ cells from CML patients (GSE4170) were analyzed only for samples that were known to be in blast crisis (BC)
BCR-ABL exhibits constitutive tyrosine kinase activity resulting in the development of leukemia through the stimulation of proliferative signaling pathways in the myeloid lineage

Summary

Introduction

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell malignancy characterized by the presence of the chromosomal translocation t(9;22) generating Philadelphia (Ph1) chromosome in all leukemic cells [1]. A major issue remaining today in the CML field is the persistence of stem cells event in deep molecular response due to the resistance of leukemic stem cells to TKI currently in use [4,5]. This could be associated with clinical resistance in the context of TKI therapies with emergence of resistant clones from the initial CML stem cell clone, which has an inherent predisposition to genetic instability. We characterized a stem cell program activated during CML blast crisis shared between chromatin binding of TCF7L2 and MYC This transcriptional program defined to be independent of the adult hematopoietic program driven by RUNX1 and GATA2 and included epigenetics actors, which mainly implicated arginine methylation mechanism. Some TCF7L2 cis distal active enhancer like elements were found near genomic regions of transcription factors activated during blast crisis

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