Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid.
The expression of Bcl-2 family members was examined in normal and leukemic hematopoietic cells. Immature hematopoietic progenitor cells (CD34+/33-/13-) did not express Bcl-2 but Bcl-XL, the majority of CD34 cells expressed Bcl-2, Bcl-XL and BAD, and normal promyelocytes (CD34-/33+) lacked expression of both Bcl-2 and Bcl-XL, while leukemic CD34+progenitors and promyelocytes expressed these anti-apoptotic proteins. In AML, Bcl-2 expression was higher on CD34+ than on all AML cells, however, expression of Bcl-2 or Bcl-XL did not predict achievement of complete remission. Surprisingly, low Bcl-2 content was associated with poor survival in a group of patients with poor prognosis cytogenetics. The anti-apoptotic BAD protein was found to be expressed in AML, but was phosphorylated in 41/42 samples. Phosphorylation was found at both sites, Ser 112 and Ser 136. During induction chemotherapy, Bcl-2 levels of CD34 cells increased significantly. In the context of evidence for small numbers of leukemic CD34+ cells expressing very high levels of Bcl-2 prior to therapy, this finding is interpreted as a survival advantage of Bcl-2 overexpressing progenitors and rapid elimination of cells with low Bcl-2. Bcl-2 and Bcl-XL were both expressed in minimal residual disease cells. Downregulation of Bcl-2 mRNA and protein was observed by ATRA and the combination of Ara-C, followed by ATRA, resulted in markedly increased cytotoxicity in HL-60 cells, as compared to Ara-C alone or ATRA followed by Ara-C. Implications of these findings for the development of new therapeutic strategies for AML are discussed.
Andreeff
M
M
Department of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jiang
S
S
Zhang
X
X
Konopleva
M
M
Estrov
Z
Z
Snell
V E
VE
Xie
Z
Z
Okcu
M F
MF
Sanchez-Williams
G
G
Dong
J
J
Estey
E H
EH
Champlin
R C
RC
Kornblau
S M
SM
Reed
J C
JC
Zhao
S
S
D000208:Acute Disease; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics; D003561:Cytarabine / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D019254:Genes, bcl-2 / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D015996:Survival Rate; D014212:Tretinoin / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
D018952:Antigens, CD34; D000970:Antineoplastic Agents; C494819:BAD protein, human; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D003561:Cytarabine; D010768:Phosphoserine; D014212:Tretinoin