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.
Bibliographical noteFunding Information:
We thank Dr. Kevin Shannon for critical review of the manuscript. This work was supported by the University of Minnesota Masonic Cancer Center & Academic Health Center Flow Cytometry Resource, Research Animal Resources, and University Imaging Centers that are supported by the National Cancer Institute (P30CA77598).This work was supported by funding from the University of Minnesota Department of Medicine, Division of Hematology Oncology & Transplantation and the University of Minnesota Foundation (CEE); Leukemia & Lymphoma Society of America Specialized Center of Research LLS7019-04 (DAL); and National Heart Lung & Blood Institute T32HL007062 (CEE). DAL is an American Cancer Society Research Professor.
- Acute myeloid leukemia (AML)
- RAS signaling