Inhibiting the Palmitoylation/depalmitoylation Cycle Selectively Reduces the Growth of Hematopoietic Cells Expressing Oncogenic Nras

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2011 Dec 7

PMID 22144181

Citations 40

Authors

Jin Xu

Christian Hedberg

Frank J Dekker

Qing Li

Kevin M Haigis

Eugene Hwang

Herbert Waldmann

Kevin Shannon

Affiliations

Soon will be listed here.

Abstract

The palmitoylation/depalmitoylation cycle of posttranslational processing is a potential therapeutic target for selectively inhibiting the growth of hematologic cancers with somatic NRAS mutations. To investigate this question at the single-cell level, we constructed murine stem cell virus vectors and assayed the growth of myeloid progenitors. Whereas cells expressing oncogenic N-Ras(G12D) formed cytokine-independent colonies and were hypersensitive to GM-CSF, mutations within the N-Ras hypervariable region induced N-Ras mislocalization and attenuated aberrant progenitor growth. Exposing transduced hematopoietic cells and bone marrow from Nras and Kras mutant mice to the acyl protein thioesterase inhibitor palmostatin B had similar effects on protein localization and colony growth. Importantly, palmostatin B-mediated inhibition was selective for Nras mutant cells, and we mapped this activity to the hypervariable region. These data support the clinical development of depalmitoylation inhibitors as a novel class of rational therapeutics in hematologic malignancies with NRAS mutations.

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