Decreased expression level of SH2 domain-containing protein tyrosine phosphatase-1 (Shp1) is associated with progression of chronic myeloid leukaemia.
Chronic myeloid leukaemia (CML) is characterized by t(9;22)(q34;q11) and the aberrant expression of the fusion protein Bcr-Abl that leads to constitutive activation of c-Abl kinase. Bcr-Abl plays a major role in the development and progression of CML through chronic, accelerated, and blast phases. The interaction between Bcr-Abl and other oncogenic molecules has been extensively documented. Nonetheless, negative regulatory mechanisms of Bcr-Abl are not completely defined. One major inhibitory pathway is mediated via the SH2 domain-containing protein tyrosine phosphatase Shp1. In the present study, we demonstrate that Shp1 levels are markedly decreased in advanced stage CML patients compared with those in chronic phase. This process was independent of DNA methylation. Furthermore, we did not detect mutations in the Shp1 gene in CML cell lines or patient samples. These data suggest that the decrease in Shp1 in advanced stage CML patients is due to post-transcriptional modifications. Our findings suggest that the decrease in Shp1 expression levels plays a role in the progression of CML. Also, the decrease in Shp1 and subsequently its inhibitory effect on Bcr-Abl could provide an explanation for imatinib resistance seen in advanced stage CML patients.
Amin
H M
HM
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. hamin@mdanderson.org
Hoshino
K
K
Yang
H
H
Lin
Q
Q
Lai
R
R
Garcia-Manero
G
G
D000328:Adult; D000368:Aged; D019175:DNA Methylation; D004252:DNA Mutational Analysis / Q000379:methods; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D018076:DNA, Complementary; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6