Relative Mitochondrial Priming of Myeloblasts and Normal HSCs Determines Chemotherapeutic Success in AML

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Oct 16

PMID 23063124

Citations 204

Authors

Thanh-Trang Vo

Jeremy Ryan

Ruben Carrasco

Donna Neuberg

Derrick J Rossi

Richard M Stone

Daniel J DeAngelo

Mark G Frattini

Anthony Letai

Affiliations

Soon will be listed here.

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:

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