Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML Journal Article
| Authors: | Vo, T. T.; Ryan, J.; Carrasco, R.; Neuberg, D.; Rossi, D. J.; Stone, R. M.; DeAngelo, D. J.; Frattini, M. G.; Letai, A. |
| Article Title: | Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML |
| Abstract: | Despite decades of successful use of cytotoxic chemotherapy in acute myelogenous leukemia (AML), the biological basis for its differential success among individuals and for the existence of a therapeutic index has remained obscure. Rather than taking a genetic approach favored by many, we took a functional approach to ask how differential mitochondrial readiness for apoptosis ("priming") might explain individual variation in clinical behavior. We found that mitochondrial priming measured by BH3 profiling was a determinant of initial response to induction chemotherapy, relapse after remission, and requirement for allogeneic bone marrow transplantation. Differential priming between malignant myeloblasts and normal hematopoietic stem cells supports a mitochondrial basis to the therapeutic index for chemotherapy. BH3 profiling identified BCL-2 inhibition as a targeted strategy likely to have a useful therapeutic index. BH3 profiling refines predictive information provided by conventional biomarkers currently in use and thus may itself have utility as a clinical predictive biomarker. PaperClip: © 2012 Elsevier Inc. |
| Keywords: | controlled study; acute granulocytic leukemia; human cell; leukemia, myeloid, acute; cytarabine; cell function; protein bcl 2; apoptosis; relapse; allogenic bone marrow transplantation; hematopoietic stem cell transplantation; cell differentiation; antineoplastic activity; cancer cell culture; drug resistance, neoplasm; tumor cells, cultured; cell line, tumor; hematopoietic stem cells; remission; predictor variable; 5 aza 2' deoxycytidine; hematopoietic stem cell; mitochondria; proto-oncogene proteins c-bcl-2; mitochondrion; clofarabine; azacitidine; topoisomerase ii inhibitors; bh3 protein; granulocyte precursor cells; myeloblast |
| Journal Title: | Cell |
| Volume: | 151 |
| Issue: | 2 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2012-10-12 |
| Start Page: | 344 |
| End Page: | 355 |
| Language: | English |
| DOI: | 10.1016/j.cell.2012.08.038 |
| PROVIDER: | scopus |
| PUBMED: | 23063124 |
| PMCID: | PMC3534747 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2012" - "CODEN: CELLB" - "Source: Scopus" |
