Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML.
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:
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Thanh-Trang
TT
Vo
Jeremy
J
Ryan
Ruben
R
Carrasco
Donna
D
Neuberg
Derrick J
DJ
Rossi
Richard M
RM
Stone
Daniel J
DJ
Deangelo
Mark G
MG
Frattini
Anthony
A
Letai
D017209:Apoptosis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D042381:Granulocyte Precursor Cells / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology* / Q000628:therapy; D008928:Mitochondria / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D059005:Topoisomerase II Inhibitors / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D019253:Proto-Oncogene Proteins c-bcl-2; D059005:Topoisomerase II Inhibitors