A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation

被引:163
作者
Notari, M
Neviani, P
Santhanam, R
Blaser, BW
Chang, JS
Galietta, A
Willis, AE
Roy, DC
Caligiuri, MA
Marcucci, G
Perrotti, D
机构
[1] Ohio State Univ, Dept Internal Med, Human Canc Genet Program, Dept Mol Virol Immunol & Med Genet,Div Hematol On, Columbus, OH USA
[2] Ohio State Univ, CCC, Columbus, OH USA
[3] Univ Nottingham, Sch Pharm, Nottingham, England
[4] Univ Montreal, Div Hematol Immunol, Maisonneuve Rosemont Hosp Res Ctr, Dept Med, Montreal, PQ, Canada
关键词
D O I
10.1182/blood-2005-09-3732
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Altered mRNA translation is one of the effects exerted by the BCR/ABL oncoprotein in the blast crisis phase of chronic myelogenous leukemia (CML). Here, we report that in BCR/ABL(+) cell lines and in patient-derived CML blast crisis mononuclear and CD34(+) cells, p210(BCR/ABL) increases expression and activity of the transcriptional-inducer and translational-regulator heterogeneous nuclear ribonucleoprotein K (hnRNP K or HNRPK) in a dose- and kinase-dependent manner through the activation of the MAPK(ERK1/2) pathway. Furthermore, HNRPK down-regulation and interference with HNRPK translation- but not transcription-regulatory activity impairs cytokine-independent proliferation, clonogenic potential, and in vivo leukemogenic activity of BCR/ABIL-expressing myeloid 32Dcl3 and/or primary CD34(+) CML-BC patient cells. Mechanistically, we demonstrate that decreased internal ribosome entry site (IRES)-dependent Myc mRNA translation accounts for the phenotypic changes induced by inhibition of the BCR/ABL-ERK-dependent HNRPK translation-regulatory function. Accordingly, MYC protein butnot mRNA levels are increased in the CD34(+) fraction of patients with CML in accelerated and blastic phase but not in chronic phase CML patients and in the CD34(+) fraction of marrow cells from healthy donors. Thus, BCR/ABL-dependent enhancement of HNRPK translation-regulation is important for BCR/ABL leukemogenesis and, perhaps, it might contribute to blast crisis transformation.
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页码:2507 / 2516
页数:10
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