A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation.
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/ABL-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 but not 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.
Notari
Mario
M
Human Cancer Genetics Program, The Ohio State University Medical Center, Columbus, OH 43240, USA.
Neviani
Paolo
P
Santhanam
Ramasamy
R
Blaser
Bradley W
BW
Chang
Ji-Suk
JS
Galietta
Annamaria
A
Willis
Anne E
AE
Roy
Denis C
DC
Caligiuri
Michael A
MA
Marcucci
Guido
G
Perrotti
Danilo
D
D018952:Antigens, CD34; D001752:Blast Crisis / Q000209:etiology; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D014176:Protein Biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012261:Ribonucleoproteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012261:Ribonucleoproteins; C072074:HNRNPK protein, human; D016044:Fusion Proteins, bcr-abl; D020928:Mitogen-Activated Protein Kinases