Jak2 inhibition deactivates Lyn kinase through the SET-PP2A-SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients.
Chronic myelogenous leukemia (CML) patients treated with imatinib mesylate (IM) become drug resistant by mutations within the kinase domain of Bcr-Abl, and by other changes that cause progression to advanced stage (blast crisis) and increased expression of the Lyn tyrosine kinase, the regulation of which is not understood yet. In Bcr-Abl+ cells inhibition of Jak2, a downstream target of Bcr-Abl, by either Jak2 inhibitors or Jak2-specific short interfering RNA (siRNA) reduced the level of the SET protein, and increased PP2A Ser/Thr phosphatase and Shp1 tyrosine phosphatase activities, which led to decreased levels of activated Lyn. Activation of PP2A combined with Jak2 inhibition enhanced the reduction of activated Lyn kinase compared with Jak2 inhibition alone. In contrast, inhibition of either PP2A or Shp1 combined with Jak2 inhibition interfered with the loss of Lyn kinase activation more so than Jak2 inhibition alone, indicating the involvement of PP2A and Shp1 in the inactivation of the Lyn kinase caused by Jak2 inhibition. Inhibition of Jak2 induced apoptosis and reduced colony formation in IM-sensitive and -resistant Bcr-Abl mutant cell lines. Jak2 inhibition also induced apoptosis in CML cells from blast crisis patients but not in normal hematopoietic cells. These results indicate that Lyn is downstream of Jak2, and Jak2 maintains activated Lyn kinase in CML through the SET-PP2A-Shp1 pathway.
Samanta
A K
AK
Department of Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Chakraborty
S N
SN
Wang
Y
Y
Kantarjian
H
H
Sun
X
X
Hood
J
J
Perrotti
D
D
Arlinghaus
R B
RB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology*; D003510:Cyclohexanes / Q000494:pharmacology; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D056488:Histone Chaperones; D006801:Humans; D000068877:Imatinib Mesylate; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000502:physiology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism*
C500162:1,2,3,4,5,6-hexabromocyclohexane; D001549:Benzamides; D002868:Chromosomal Proteins, Non-Histone; D003510:Cyclohexanes; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D010879:Piperazines; D011743:Pyrimidines; C513473:SET protein, human; D014157:Transcription Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000068877:Imatinib Mesylate; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6