Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid (original) (raw)
- Original Manuscript
- Published: 03 November 1999
Gieseler Papers on Apoptosis Research
- S Jiang1,
- X Zhang1,
- M Konopleva1,
- Z Estrov2,
- VE Snell1,
- Z Xie1,
- MF Okcu1,
- G Sanchez-Williams1,
- J Dong3,
- EH Estey4,
- RC Champlin5,
- SM Kornblau1,
- JC Reed6 &
- …
- S Zhao1
Leukemia volume 13, pages 1881–1892 (1999)Cite this article
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Abstract
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.
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Authors and Affiliations
- Department of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
M Andreeff, S Jiang, X Zhang, M Konopleva, VE Snell, Z Xie, MF Okcu, G Sanchez-Williams, SM Kornblau & S Zhao - Department of Bioimmunotherapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Z Estrov - Department of Biomathematics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
J Dong - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
EH Estey - Department of Blood and Marrow Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
RC Champlin - Burnham Institute, La Jolla, California, USA
JC Reed
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Andreeff, M., Jiang, S., Zhang, X. et al. Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid.Leukemia 13, 1881–1892 (1999). https://doi.org/10.1038/sj.leu.2401573
- Received: 12 August 1998
- Accepted: 12 July 1999
- Published: 03 November 1999
- Issue Date: 01 November 1999
- DOI: https://doi.org/10.1038/sj.leu.2401573