TY - JOUR
T1 - Expression of Bcl-2-related genes in normal and AML progenitors
T2 - Changes induced by chemotherapy and retinoic acid
AU - Andreeff, M.
AU - Jiang, S.
AU - Zhang, X.
AU - Konopleva, M.
AU - Estrov, Z.
AU - Snell, V. E.
AU - Xie, Z.
AU - Okcu, M. F.
AU - Sanchez-Williams, G.
AU - Dong, J.
AU - Estey, E. H.
AU - Champlin, R. C.
AU - Kornblau, S. M.
AU - Reed, J. C.
AU - Zhao, S.
N1 - Funding Information:
This work was supported in part by grants from the National Institutes of Health (PO1 CA55164, PO1 CA49639, and CA16672) and from the Stringer Professorship for Cancer Treatment and Research (MA).
PY - 1999
Y1 - 1999
N2 - 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-X(L), the majority of CD34 cells expressed Bcl-2, Bcl-X(L) and BAD, and normal promyelocytes (CD34-/33+) lacked expression of both Bcl-2 and Bcl-X(L), 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-X(L) 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-X(L) 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.
AB - 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-X(L), the majority of CD34 cells expressed Bcl-2, Bcl-X(L) and BAD, and normal promyelocytes (CD34-/33+) lacked expression of both Bcl-2 and Bcl-X(L), 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-X(L) 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-X(L) 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.
KW - AML
KW - Apoptosis
KW - BAD
KW - Bcl-2
KW - Bcl-X(L)
KW - Minimal residual disease
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U2 - 10.1038/sj.leu.2401573
DO - 10.1038/sj.leu.2401573
M3 - Article
C2 - 10557066
AN - SCOPUS:0032721858
SN - 0887-6924
VL - 13
SP - 1881
EP - 1892
JO - Leukemia
JF - Leukemia
IS - 11
ER -