Effect of Ras Inhibition in Hematopoiesis and BCR/ABL Leukemogenesis

Karina J Baum,Ruibao Ren

doi:10.1186/1756-8722-1-5

Abstract

Ras small GTPases are activated in many hematopoietic growth factor signaling and in hematological malignancies, but their role in hematopoiesis and leukemogenesis is not completely known. Here we examined the effect of Ras inhibition by a dominant negative mutant of Ras, N17 H-Ras, in adult hematopoiesis and in BCR/ABL leukemogenesis using the mouse bone marrow transduction and transplantation approach. We found that N17 H-Ras expression suppressed B- and T-lymphopoiesis and erythropoiesis. Interestingly, N17 H-Ras did not suppress myelopoiesis in the bone marrow, yet it greatly attenuated BCR/ABL-induced chronic myelogenous leukemia (CML)-like myeloproliferative disease. Most BCR/ABL + N17 H-Ras mice eventually developed pro-B lymphoblastic leukemia/lymphoma (B-ALL). These results suggest that Ras activation is essential for the development of lymphoid and erythroid cells but not myeloid cells and that Ras is a critical target of BCR/ABL in the pathogenesis of CML, but not B-ALL.

Highlights

Ras proteins are small GTPases that act as molecular switches, transducing signals from activated receptors to downstream effectors to regulate cell proliferation, survival and differentiation [1]
To assess the role of Ras in adult hematopoiesis and in breakpoint cluster region gene (BCR)/ABL leukemogenesis, and to assess the importance of Ras as a therapeutic target, we examined the effect of N17 H-Ras mutant in bone marrow reconstitution and in the induction of chronic myelogenous leukemia (CML)-like myeloproliferative disease (MPD) by BCR/ABL in mice
Expression of N17 H-Ras inhibits hematopoiesis Prior to examine the role of Ras activation in BCR/ABL leukemogenesis using N17 H-Ras, we examined the effect of N17 H-Ras in hematopoiesis

Summary

Introduction

Ras proteins are small GTPases that act as molecular switches, transducing signals from activated receptors to downstream effectors to regulate cell proliferation, survival and differentiation [1]. The four Ras proteins share an identical amino-terminal region This region includes the nucleotide binding and effector loop domains, providing a basis for the ability of Ras proteins to interact with a common set of activators and effectors and to share many biochemical and biological functions. The 80 amino acids are highly homologous (85% identity) among all four Ras proteins. The Ras proteins diverge highly at the carboxyl-terminal 23–24 amino acids, referred to as the hypervariable domain (HVR) [4]. This HVR domain signals the posttranslational modifications that enable the Ras proteins to attach to the inner surface of the plasma membrane, a prerequisite for Ras-mediated signal transduction. Different modifications and targeting mechanisms result in localization of the Ras proteins to functionally distinct microdomains of the plasma membrane, which may allow the Ras proteins access to different pools of Ras regulators and/or effectors and, generate distinct signal outputs [3]

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Conclusion