Oncogenic RAS enables DNA damage- and p53-dependent differentiation of acute myeloid leukemia cells in response to chemotherapy.
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.
Meyer
Mona
M
Klinik für Hämatologie, Onkologie und Immunologie, Philipps Universität Marburg, Marburg, Germany.
Rübsamen
Daniela
D
Slany
Robert
R
Illmer
Thomas
T
Stabla
Kathleen
K
Roth
Petra
P
Stiewe
Thorsten
T
Eilers
Martin
M
Neubauer
Andreas
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D049109:Cell Proliferation; D016922:Cellular Senescence; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D011905:Genes, ras; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D003561:Cytarabine; D005047:Etoposide; D018631:ras Proteins; D003630:Daunorubicin