MR-1 blocks the megakaryocytic differentiation and transition of CML from chronic phase to blast crisis through MEK dephosphorylation

W Zhao,B Li,Y Lin,K Ren,H He,R-G Shao,H Zhang

doi:10.1038/bcj.2013.5

Abstract

Chronic myelogenous leukemia (CML) evolves from a chronic phase characterized by the Philadelphia chromosome as the sole genetic abnormality and the accumulation of mature cells in peripheral blood into blast crisis, which is characterized by the rapid expansion of myeloid- or lymphoid-differentiation-arrested blast cells. Although ample studies have been conducted on the disease progress mechanisms, the underlying molecular mechanisms of the malignant phenotype transition are still unclear. In this study, we have shown that myofibrillogenesis regulator-1 (MR-1) was overexpressed in blast crisis patients and leukemic cells, but there was little trace expressed in healthy individuals and in most patients in CML chronic phase. MR-1 could inhibit the differentiation of myeloid cells into megakaryocytic lineages and accelerate cell proliferation. The molecular mechanism responsible for these effects was the interaction of MR-1 with MEK, which blocked the MEK/ERK signaling pathway by dephosphorylating MEK. Our results provide compelling and important evidence that MR-1 might act as a diagnostic marker and potential target of CML progression from chronic phase to blast crisis.

Highlights

Chronic myelogenous leukemia (CML), a clonal myeloproliferative disorder of hematopoietic stem cells, is initially typically seen in a relatively benign chronic state, but turns into fatal blast crisis.[1]
We verified that myofibrillogenesis regulator-1 (MR-1) was overexpressed in blast crisis patients and cell lines of CML but was not expressed or there was little trace of it in healthy individuals and in most patients in the chronic phase of CML
MR-1 is overexpressed in blast crisis cells and downregulated in PMA-treated cells

Summary

INTRODUCTION

Chronic myelogenous leukemia (CML), a clonal myeloproliferative disorder of hematopoietic stem cells, is initially typically seen in a relatively benign chronic state, but turns into fatal blast crisis.[1]. Myofibrillogenesis regulator-1 (MR-1) was identified from a human skeletal muscle cDNA library (GenBank accession number AF417001) and is located on human chromosome 2q35 (GenBank accession number AC021016).[3] MR-1 was seen to be overexpressed in human cancer cells.[4] The ability of cell proliferation was decreased by MR-1 knockdown in human hepatoma cells and ovarian cancer cells.[4,5] Our previous results revealed that MR-1 was almost undetectable in normal human lung fibroblasts and spleen cells but was overexpressed in human embryonic lung fibroblast cells and in some acute leukemic cell lines It suggests that expression of MR-1 in normal tissue is low but is higher in its corresponding malignant or original tissue, hinting that MR-1 may be a proliferation- and differentiation-related gene and may participate in leukemic initiation and development. The knockdown of MR-1 inhibited proliferation and induced blast cell differentiation forward MK lineage through activation of the MEK/ERK signaling pathway induced by the upregulation of MEK phosphorylation

MATERIALS AND METHODS

13 BC-CML 58 F

RESULTS

CONFLICT OF INTEREST