A specific need for CRKL in p210BCR-ABL-induced transformation of mouse hematopoietic progenitors.
CRKL (CRK-like) is an adapter protein predominantly phosphorylated in cells that express the tyrosine kinase p210(BCR-ABL), the fusion product of a (9;22) chromosomal translocation causative for chronic myeloid leukemia. It has been unclear, however, whether CRKL plays a functional role in p210(BCR-ABL) transformation. Here, we show that CRKL is required for p210(BCR-ABL) to support interleukin-3-independent growth of myeloid progenitor cells and long-term outgrowth of B-lymphoid cells from fetal liver-derived hematopoietic progenitor cells. Furthermore, a synthetic phosphotyrosyl peptide that binds to the CRKL SH2 domain with high affinity blocks association of endogenous CRKL with the p210(BCR-ABL) complex and reduces c-MYC levels in K562 human leukemic cells as well as in mouse hematopoietic cells transformed by p210(BCR-ABL) or the imatinib-resistant mutant T315I. These results indicate that the function of CRKL as an adapter protein is essential for p210(BCR-ABL)-induced transformation.
Seo
Ji-Heui
JH
Ben May Department for Cancer Research, Committees on Developmental Biology, Genetics, Cancer Biology, and Cell Physiology, University of Chicago, Chicago, IL 60637, USA.
Wood
Lisa J
LJ
Agarwal
Anupriya
A
O'Hare
Thomas
T
Elsea
Collin R
CR
Griswold
Ian J
IJ
Deininger
Michael W N
MW
Imamoto
Akira
A
Druker
Brian J
BJ
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D020014:K562 Cells; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D007377:Interleukin-3; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D050799:STAT5 Transcription Factor; D051020:bcl-X Protein; D016044:Fusion Proteins, bcr-abl
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