Inhibition of signal transducer and activator of transcription 5 by the inhibitor of janus kinases stimulates dormant human leukemia CD34+ /CD38- cells and sensitizes them to antileukemia agents.
To verify molecular mechanisms by which leukemia stem cells (LSCs) maintain a dormant state, we explored the activity of the major prosurvival signal pathways in CD34(+) /CD38(-) compartment, supposed to contain LSCs, and CD34(+) /CD38(+) counterparts from patients with acute myelogenous leukemia (AML, n = 11) by fluorescence-activated cell sorting (FACS). CD34(+) /CD38(-) cells expressed a greater amount of p-janus kinase 2 (JAK2) and p-signal transducer and activator of transcription 5 (STAT5) than CD34(+) /CD38(+) counterparts in all patients except for one case. In addition, we found that CD34(+) /CD38(-) cells were relatively resistant to cytarabine- and the inhibitor of the fms-like tyrosine kinase 3 (FLT3)-mediated growth inhibition, as measured by the clonogenic assay. Interestingly, blockade of JAK2/STAT5 signaling by the specific JAK2 inhibitor AZ960 stimulated cell cycling in CD34(+) /CD38(-) cells in conjunction with downregulation of cyclin-dependent kinase inhibitor p21(waf1) and sensitized these cells to the growth inhibition mediated by cytarabine and the FLT3 kinase inhibitor. Moreover, exposure of CD34(+) /CD38(-) cells to AZ960 potently induced apoptosis in parallel with downregulation of antiapoptotic protein Bcl-xL, as measured by Western blot analysis. Taken together, JAK2/STAT5 signaling may be a promising molecular target to eradicate CD34(+) /CD38(-) leukemia cells in individuals with AML.
Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan. ikezoet@kochi-u.ac.jp
Takayuki
T
Ikezoe
Jing
J
Yang
Chie
C
Nishioka
Shinsuke
S
Kojima
Asako
A
Takeuchi
H
H
Phillip Koeffler
Akihito
A
Yokoyama
D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology*; D000368:Aged; D018952:Antigens, CD34 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D007938:Leukemia / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors*
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D053614:Janus Kinase 2; D051997:ADP-ribosyl Cyclase 1