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.
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.
Marina
M
Konopleva
Shourong
S
Zhao
Wei
W
Hu
Shuwei
S
Jiang
Virginia
V
Snell
Douglas
D
Weidner
C Ellen
CE
Jackson
Xin
X
Zhang
Richard
R
Champlin
Elihu
E
Estey
John C
JC
Reed
Michael
M
Andreeff
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