GSE161614
CUX1 deficiency potentiates RAS signaling to drive malignancy
-7/del(7q) is genetic event prevalent in high-risk myeloid neoplasms. For reasons that are unclear, gain-of-function mutations in the RAS pathway frequently co-occur with monosomy 7.  Here we identify a genetic interaction between RAS and the 7q-encoded transcription factor, CUX1.  Concomitant mutations in RAS genes and CUX1 are wide-spread across tumor types, suggesting cooperativity in tumorigenesis.   To test this, we generated mice with oncogenic NrasG12D and Cux1 knockdown. Double mutant mice developed myeloid malignancies with higher penetrance and faster onset than either single allele alone, with leukemic transformation in one third of cases. Oncogenic RAS imparts increased self-renewal on CUX1-deficient hematopoietic stem and progenitor cells (HSPCs).  Reciprocally, CUX1 knockdown amplifies RAS signaling through decreased transcriptional expression of negative regulators of RAS and PI3K signaling.  Accordingly, NrasG12D;Cux1-knockdown HSPCs have heighted growth factor-sensitivity and downstream RAS pathway activation.  Double mutant HSPCs were responsive to PIK3 or MEK inhibition, suggesting that these may be promising therapeutic targets in patients with ­7/del(7q) malignancies.  Our results implicate the loss of CUX1 as the underlying explanation for the association of -7/del(7q) with oncogenic RAS.  Furthermore, we report the unexpected convergence of an oncogene and tumor suppressor gene on the same pathway. Overall design: RNA-seq of HSPCs from Cux1-low and Cux1-low;NrasG12D mice