Journal
LEUKEMIA
Volume 18, Issue 4, Pages 727-733Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.leu.2403310
Keywords
CML; BCR-ABL; mRNA splicing; Pyk2; CD34(+) cells
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Funding
- NCI NIH HHS [CA09138] Funding Source: Medline
- NHLBI NIH HHS [R01 HL-49930] Funding Source: Medline
- NIDDK NIH HHS [R01 DK-53673] Funding Source: Medline
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Chronic myelogenous leukemia (CML) is a malignancy of the human hematopoietic stem cell (HSC) caused by the p210(BCR/ABL) oncoprotein. Although alternative splicing of pre-mRNA is a critical determinant of a cell's protein repertoire, it has not been associated with CML pathogenesis. We identified a BCR/ABL-dependent increase in expression of multiple genes involved in pre-mRNA splicing (eg SRPK1, RNA Helicase II/Gu, and hnRNPA2/B1) by subtractive hybridization of cDNA from p210(BCR/ABL)-eGFP vs eGFP-transduced umbilical cord blood CD34(+) cells. beta1-integrin signaling is important to HSC maintenance and proliferation/differentiation, and is abnormal in CML. As an example of how changes in pre-mRNA processing might contribute to CML pathogenesis, we observed alternative splicing of a gene for a beta1-integrin-responsive nonreceptor tyrosine kinase (PYK2), resulting in increased expression of full-length Pyk2 in BCR/ABL-containing cells. Treatment of p210(BCR/ABL)-positive cells with the Abl-specific tyrosine kinase inhibitor STI571 reverted PYK2 splicing to a configuration more consistent with normal cells, and correlated with decreased expression of BCR/ABL-induced proteins involved in pre-mRNA processing. Whether altered PYK2 splicing contributes to CML pathogenesis remains undetermined; however, we propose that generic changes in pre-mRNA splicing as a result of p210(BCR/ABL) kinase activity may contribute to CML pathogenesis.
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