Synergism between NRAS and IL7R drives acute lymphoblastic leukemia

Authors

• W Li
• H Winer
• G Rodrigues
• T Gower
• TJ Meyer
• J Hixon
• SK Durum

Abstract

Acute lymphoblastic leukemia (ALL) is an aggressive leukemia derived from either T-cell or B-cell precursors. Mutations in the Ras pathway frequently occurred with IL-7R gain-of-function mutation (mutIL7R) in ALL. To understand the synergistic mechanism of mutant NRAS (mutNRAS) and mutIL7R in ALL, immature mouse thymocytes were transduced with mutIL7R, mutNRAS or their combination and transplanted into RAG-/- mice. Transcriptome and proteome analysis showed a significant increase in IL7R mediated BCL2 expression, and an increase in MYC protein level which was mainly induced by NRAS signaling. mutNRAS promotes MYC protein stability by activating Raf-MEK-ERK signaling which is known to phosphorylate MYC at Serine 62. MYC overexpression phenocopied mutNRAS in its ability to collaborate with mutIL7R to drive T-ALL in mice, with CD4+CD8+ phenotype and relatively similar expression of TCR αβ and γδ T-cells. Myc deletion decreased leukemia burden in vivo and that Myc silencing decreased the viability of a thymic cell line D1 and the primary thymocytes transduced with the combination of the two oncogenes. PLK1 kinase was significantly increased in cells transduced with either mutNRAS alone or both mutations combined, which implicates PLK1 regulation by RAS signaling, which is then responsible for MYC protein stabilization. Volasertib, a PLK1 inhibitor, diminished MYC levels and leukemia burden in our mutIL7R+mutNRAS T-ALL mouse model. Our studies not only identify novel pathways of how NRAS signaling cooperated with oncogenic IL7R in driving ALL, but also pave the way for preclinical studies testing the value of PLK1 and/or MYC inhibitors in ALL treatment.

Scientific Focus Area: Cancer Biology

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