RALB provides critical survival signals downstream of Ras in acute myeloid leukemia
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Craig E. Eckfeldt1,2, Emily J. Pomeroy1, Robin D.W. Lee1, Katherine S. Hazen1, Lindsey A. Lee1, Branden S. Moriarity2,3, David A. Largaespada2,3,4
1Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA
2Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
3Department of Pediatrics, Division of Hematology and Oncology, University of Minnesota, Minneapolis, MN 55455, USA
4Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA
Craig E. Eckfeldt, email: firstname.lastname@example.org
Keywords: RAS signaling, RALB, TBK1, BCL2, acute myeloid leukemia (AML)
Received: April 20, 2016 Accepted: August 11, 2016 Published: August 20, 2016
Mutations that activate RAS proto-oncogenes and their effectors are common in acute myeloid leukemia (AML); however, efforts to therapeutically target Ras or its effectors have been unsuccessful, and have been hampered by an incomplete understanding of which effectors are required for AML proliferation and survival. We investigated the role of Ras effector pathways in AML using murine and human AML models. Whereas genetic disruption of NRAS(V12) expression in an NRAS(V12) and Mll-AF9-driven murine AML induced apoptosis of leukemic cells, inhibition of phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) signaling did not reproduce this effect. Conversely, genetic disruption of RALB signaling induced AML cell death and phenocopied the effects of suppressing oncogenic Ras directly – uncovering a novel role for RALB signaling in AML survival. Knockdown of RALB led to decreased phosphorylation of TBK1 and reduced BCL2 expression, providing mechanistic insight into RALB survival signaling in AML. Notably, we found that patient-derived AML blasts have higher levels of RALB-TBK1 signaling compared to normal blood leukocytes, supporting a pathophysiologic role for RALB signaling for AML patients. Overall, our work provides new insight into the specific roles of Ras effector pathways in AML and has identified RALB signaling as a key survival pathway.
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