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Oncogenic RAS promotes leukemic transformation of CUX1-deficient cells
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Journal Article
Oncogenic RAS promotes leukemic transformation of CUX1-deficient cells
2023
Overview
-7/del(7q) is prevalent across subtypes of myeloid neoplasms.
CUX1
, located on 7q22, encodes a homeodomain-containing transcription factor, and, like -7/del(7q),
CUX1
inactivating mutations independently carry a poor prognosis. As with loss of 7q,
CUX1
mutations often occur early in disease pathogenesis. We reported that CUX1 deficiency causes myelodysplastic syndrome in mice but was insufficient to drive acute myeloid leukemia (AML). Given the known association between -7/del(7q) and RAS pathway mutations, we mined cancer genome databases and explicitly linked
CUX1
mutations with oncogenic RAS mutations. To determine if activated RAS and CUX1 deficiency promote leukemogenesis, we generated mice bearing
Nras
G12D
and CUX1-knockdown which developed AML, not seen in mice with either mutation alone. Oncogenic RAS imparts increased self-renewal on CUX1-deficient hematopoietic stem/progenitor cells (HSPCs). Reciprocally, CUX1 knockdown amplifies RAS signaling through reduction of negative regulators of RAS/PI3K signaling. Double mutant HSPCs were responsive to PIK3 or MEK inhibition. Similarly, low expression of
CUX1
in primary AML samples correlates with sensitivity to the same inhibitors, suggesting a potential therapy for malignancies with
CUX1
inactivation. This work demonstrates an unexpected convergence of an oncogene and tumor suppressor gene on the same pathway.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
1-Phosphatidylinositol 3-kinase
/ 13/100
/ 13/31
/ 13/44
/ 45/91
/ 64/60
/ 96/1
/ 96/106
/ Animals
/ Genomes
/ Hematopoietic Stem Cells - metabolism
/ Homeobox
/ Leukemia, Myeloid, Acute - genetics
/ Leukemia, Myeloid, Acute - metabolism
/ Medicine
/ Mice
/ Mutation
/ Oncology
/ Phosphatidylinositol 3-Kinases - metabolism
/ Transcription Factors - genetics
