Abstract
Acute myeloid leukemia (AML) is a clonal disease originating from myeloid progenitor cells with a heterogeneous genetic background. High-dose cytarabine is used as the standard consolidation chemotherapy. Oncogenic RAS mutations are frequently observed in AML, and are associated with beneficial response to cytarabine. Why AML-patients with oncogenic RAS benefit most from high-dose cytarabine post-remission therapy is not well understood. Here we used bone marrow cells expressing a conditional MLL-ENL-ER oncogene to investigate the interaction of oncogenic RAS and chemotherapeutic agents. We show that oncogenic RAS synergizes with cytotoxic agents such as cytarabine in activation of DNA damage checkpoints, resulting in a p53-dependent genetic program that reduces clonogenicity and increases myeloid differentiation. Our data can explain the beneficial effects observed for AML patients with oncogenic RAS treated with higher dosages of cytarabine and suggest that induction of p53-dependent differentiation, e.g. by interfering with Mdm2-mediated degradation, may be a rational approach to increase cure rate in response to chemotherapy. The data also support the notion that the therapeutic success of cytotoxic drugs may depend on their ability to promote the differentiation of tumor-initiating cells.
Highlights
Acute myeloid leukemia (AML) is a clonal disease with a heterogeneous genetic background
Using AML samples taken from this study, we have previously shown that AML patients harboring oncogenic RAS show significantly less cumulative incidence of relapse upon treatment with high-dose cytarabine in the post-induction chemotherapy, when compared to AML patients with oncogenic RAS treated with low-dose cytarabine
Oncogenic RAS mutations are among the most frequent mutations observed in human cancers
Summary
Acute myeloid leukemia (AML) is a clonal disease with a heterogeneous genetic background. Cytogenetic alterations and molecular lesions such as mutations in the FLT-3 or nucleophosmin genes play a pivotal role in predicting treatment response ([1]; reviewed in [2,3]). Class I mutations that affect genes encoding receptor tyrosine kinases (Flt-3 or Kit) or RAS are thought to induce myeloid proliferation. Class II lesions affect transcription factors such as nucleophosmin, C/EBPa, AML-ETO, MLL-ENL, PML-RARa and block differentiation Supporting this notion, oncogenic RAS alone induces a myeloproliferative state in murine models [8–12] and in cooperation with nuclear oncogenes such as PML-RARa induces acute leukemia [13]
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