Myc induced miR-144/451 contributes to the acquired imatinib resistance in chronic myelogenous leukemia cell K562.

Imatinib resistance remains the big hurdle for CML therapy. Previous study reveals that c-myc is important for bcr-abl CML cell proliferation, while its role in imatinib resistance is largely unknown. In this study, we first found that c-myc expression is upregulated in imatinib resistant K562R cells, which in turn enhances the expression of miR-144/451. Knockdown of c-myc or restoration of miR-144/451 in the K562R cells sensitizes K562R cells to imatinib therapy. Our study here reveals an regulatory pathway between myc and miR-144/451 and highlights that targeting either myc or miR-144/451 might be valuable for eliminating the imatinib resistant CML cells.

[1]  S. Pyndiah,et al.  c-MYC Suppresses BIN1 to Release Poly(ADP-Ribose) Polymerase 1: A Mechanism by Which Cancer Cells Acquire Cisplatin Resistance , 2011, Science Signaling.

[2]  N. Araki,et al.  Contribution of BCR–ABL‐independent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells , 2010, Cancer science.

[3]  E. Bandrés,et al.  MicroRNA‐451 Is Involved in the Self‐renewal, Tumorigenicity, and Chemoresistance of Colorectal Cancer Stem Cells , 2011, Stem cells.

[4]  A. Ganser,et al.  Specific inhibition of bcr-abl gene expression by small interfering RNA. , 2003, Blood.

[5]  H. Klamová,et al.  MicroRNA-451 in chronic myeloid leukemia: miR-451-BCR-ABL regulatory loop? , 2011, Leukemia research.

[6]  Pallu Reddanna,et al.  Imatinib-resistant K562 cells are more sensitive to celecoxib, a selective COX-2 inhibitor: role of COX-2 and MDR-1. , 2008, Leukemia research.

[7]  H. Drexler,et al.  BCR-ABL1-independent PI3Kinase activation causing imatinib-resistance , 2011, Journal of hematology & oncology.

[8]  M. Eilers,et al.  Negative regulation of the mammalian UV response by Myc through association with Miz-1. , 2002, Molecular cell.

[9]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[10]  J. Melo,et al.  The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. , 1996, Blood.

[11]  M. Varella‐Garcia,et al.  Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. , 2000, Blood.

[12]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[13]  George P Cobb,et al.  microRNAs as oncogenes and tumor suppressors. , 2007, Developmental biology.

[14]  Jackeline Agorreta,et al.  microRNA-451 Regulates Macrophage Migration Inhibitory Factor Production and Proliferation of Gastrointestinal Cancer Cells , 2009, Clinical Cancer Research.

[15]  H. Osada,et al.  MicroRNAs in biological processes and carcinogenesis. , 2007, Carcinogenesis.

[16]  Xiaoshuang Wang,et al.  The microRNAs involved in human myeloid differentiation and myelogenous/myeloblastic leukemia , 2008, Journal of cellular and molecular medicine.

[17]  V. Ambros The functions of animal microRNAs , 2004, Nature.

[18]  Si-yong Huang,et al.  Knockdown of SOD1 sensitizes the CD34+ CML cells to imatinib therapy , 2011, Medical oncology.

[19]  Tsung-Cheng Chang,et al.  Widespread microRNA repression by Myc contributes to tumorigenesis , 2008, Nature Genetics.

[20]  H. Klamová,et al.  Expression patterns of microRNAs associated with CML phases and their disease related targets , 2011, Molecular Cancer.

[21]  R. Pazdur,et al.  U.S. Food and Drug Administration Drug Approval Summary: conversion of imatinib mesylate (STI571; Gleevec) tablets from accelerated approval to full approval. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  R. Dildrop,et al.  Determination of the DNA sequence recognized by the bHLH-zip domain of the N-Myc protein. , 1992, Nucleic Acids Research.

[23]  M. Baccarani,et al.  c-MYC Oncoprotein Dictates Transcriptional Profiles of ATP-Binding Cassette Transporter Genes in Chronic Myelogenous Leukemia CD34+ Hematopoietic Progenitor Cells , 2011, Molecular Cancer Research.

[24]  Shaoguang Li,et al.  β-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia , 2009, Leukemia.

[25]  Hui-Kuan Lin,et al.  Jak2 is involved in c-Myc induction by Bcr-Abl , 2002, Oncogene.

[26]  Yun Dai,et al.  A Bcr/Abl-independent, Lyn-dependent Form of Imatinib Mesylate (STI-571) Resistance Is Associated with Altered Expression of Bcl-2* , 2004, Journal of Biological Chemistry.

[27]  R. Ren,et al.  Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia , 2005, Nature Reviews Cancer.

[28]  P. N. Rao,et al.  Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification , 2001, Science.

[29]  M. Pehlivan,et al.  sFRP1 promoter methylation is associated with persistent Philadelphia chromosome in chronic myeloid leukemia. , 2009, Leukemia research.

[30]  J. Massagué,et al.  Repression of p15INK4b expression by Myc through association with Miz-1 , 2001, Nature Cell Biology.

[31]  J. Massagué,et al.  Myc suppression of the p21Cip1 Cdk inhibitor influences the outcome of the p53 response to DNA damage , 2002, Nature.

[32]  Arunasree M. Kalle,et al.  Bcr-Abl-independent mechanism of resistance to imatinib in K562 cells: Induction of cyclooxygenase-2 (COX-2) by histone deacetylases (HDACs). , 2010, Leukemia research.