The Thrombopoietin/MPL/Bcl-xL Pathway is Essential for Survival and Self-renewal in Human Preleukemia Induced by AML1-ETO

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2012 Feb 17

PMID 22337712

Citations 28

Authors

Fu-Sheng Chou

Andrea Griesinger

Mark Wunderlich

Shan Lin

Kevin A Link

Mahesh Shrestha

Susumu Goyama

Benjamin Mizukawa

Shuhong Shen

Guido Marcucci

James C Mulloy

Affiliations

Soon will be listed here.

Abstract

AML1-ETO (AE) is a fusion product of translocation (8;21) that accounts for 40% of M2 type acute myeloid leukemia (AML). In addition to its role in promoting preleukemic hematopoietic cell self-renewal, AE represses DNA repair genes, which leads to DNA damage and increased mutation frequency. Although this latter function may promote leukemogenesis, concurrent p53 activation also leads to an increased baseline apoptotic rate. It is unclear how AE expression is able to counterbalance this intrinsic apoptotic conditioning by p53 to promote survival and self-renewal. In this report, we show that Bcl-xL is up-regulated in AE cells and plays an essential role in their survival and self-renewal. Further investigation revealed that Bcl-xL expression is regulated by thrombopoietin (THPO)/MPL-signaling induced by AE expression. THPO/MPL-signaling also controls cell cycle reentry and mediates AE-induced self-renewal. Analysis of primary AML patient samples revealed a correlation between MPL and Bcl-xL expression specifically in t(8;21) blasts. Taken together, we propose that survival signaling through Bcl-xL is a critical and intrinsic component of a broader self-renewal signaling pathway downstream of AML1-ETO-induced MPL.

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