The anti-apoptotic genes Bcl-X(L) and Bcl-2 are over-expressed and contribute to chemoresistance of non-proliferating leukaemic CD34+ cells.
In acute myeloid leukaemia (AML), cell kinetic quiescence has been postulated to contribute to drug resistance. As the anti-apoptotic genes Bcl-2 and Bcl-X(L) have been implicated in cell cycle regulation, we investigated the expression of these genes in non-proliferating (Q) and proliferating (P) AML and normal CD34+ progenitor cells. Using reverse transcription polymerase chain reaction, Bcl-X(L) and Bcl-2 were overexpressed in Q versus P AML cells, whereas no difference in Bcl-XS and Bax expression was found. Furthermore, the Bcl-X(L)/X(S) but not the Bcl-2/Bax ratio was higher in Q AML compared with normal CD34+ Q cells (P = 0.001). An inverse correlation between Bcl-2 expression of leukaemic Q cells and their ability to enter the cell cycle was found. Treatment with all-trans retinoic acid (ATRA) reduced Bcl-2 and Bcl-X(L) expression in the leukaemic Q cells, and enhanced their chemosensitivity to cytosine arabinoside (ara-C). These findings demonstrate overexpression of the anti-apoptotic proteins Bcl-X(L) and Bcl-2 in quiescent CD34+ AML cells and suggest their involvement in the chemoresistance. The observed inverse correlation between Bcl-2 and proliferation suggests a role for Bcl-2 in the cell cycle regulation of AML. These findings could be used in the development of therapies that selectively induce apoptosis in quiescent leukaemic progenitor cells.
Konopleva
Marina
M
Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Zhao
Shourong
S
Hu
Wei
W
Jiang
Shuwei
S
Snell
Virginia
V
Weidner
Douglas
D
Jackson
C Ellen
CE
Zhang
Xin
X
Champlin
Richard
R
Estey
Elihu
E
Reed
John C
JC
Andreeff
Michael
M
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000473:pathology; D002455:Cell Division; D003561:Cytarabine / Q000494:pharmacology; D015536:Down-Regulation; D005434:Flow Cytometry / Q000379:methods; D019254:Genes, bcl-2; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D051020:bcl-X Protein; D001613:beta 2-Microglobulin / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D018952:Antigens, CD34; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D001613:beta 2-Microglobulin; D019014:fas Receptor; D003561:Cytarabine; D014212:Tretinoin