Extensive gene-specific translational reprogramming in a model of B cell differentiation and Abl-dependent transformation.
To what extent might the regulation of translation contribute to differentiation programs, or to the molecular pathogenesis of cancer? Pre-B cells transformed with the viral oncogene v-Abl are suspended in an immortalized, cycling state that mimics leukemias with a BCR-ABL1 translocation, such as Chronic Myelogenous Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL). Inhibition of the oncogenic Abl kinase with imatinib reverses transformation, allowing progression to the next stage of B cell development. We employed a genome-wide polysome profiling assay called Gradient Encoding to investigate the extent and potential contribution of translational regulation to transformation and differentiation in v-Abl-transformed pre-B cells. Over half of the significantly translationally regulated genes did not change significantly at the level of mRNA abundance, revealing biology that might have been missed by measuring changes in transcript abundance alone. We found extensive, gene-specific changes in translation affecting genes with known roles in B cell signaling and differentiation, cancerous transformation, and cytoskeletal reorganization potentially affecting adhesion. These results highlight a major role for gene-specific translational regulation in remodeling the gene expression program in differentiation and malignant transformation.
Department of Biochemistry, Stanford University School of Medicine, Stanford, California, United States of America.
Jamie G
JG
Bates
Julia
J
Salzman
Damon
D
May
Patty B
PB
Garcia
Gregory J
GJ
Hogan
Martin
M
McIntosh
Mark S
MS
Schlissel
Pat O
PO
Brown
D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002460:Cell Line; D002472:Cell Transformation, Viral / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D020411:Oligonucleotide Array Sequence Analysis; D016374:Oncogene Proteins v-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011132:Polyribosomes / Q000187:drug effects / Q000235:genetics; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
D001549:Benzamides; D016374:Oncogene Proteins v-abl; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus