Dual inhibition of JAK and MEK suppresses T-cell acute lymphoblastic leukemia induced by mutant IL7R and RASGRP1 overexpression

Abstract

Gain-of-function mutant IL-7Rα (mutIL7R) occurs in approximately 10% of patients with Tcell acute lymphoblastic leukemia (T-ALL), an aggressive pediatric cancer. Nearly half of patients with T-ALLs also overexpress RAS guanyl nucleotide exchange factor (RASGRP1), an activator of RAS. Since mutant RAS itself has been shown to cooperate with mutIL7R in leukemogenesis, we evaluated whether RASGRP1 overexpression could do so through activation of wild type RAS. Immature murine thymocytes were transduced with mutIL7R combined with overexpression of wild type RASGRP1. The combination of the two transgenes was sufficient to induce transformation into aggressive T-ALL, whereas neither transgene alone could do so. The resulting leukemia was polyclonal with heterogeneous Tcell markers, and its subclones showed different clinical behaviors as do genetic subtypes of patient T-ALLs. Like a leukemia model driven by NRASG13D and mutIL-7R, overexpression of RASGRP1 increased ERK1/2 phosphorylation and enriched RAS gene expression signature. The leukemia driven by mutIL7R and RASGRP1 was susceptible to ruxolitinib inhibition of Janus kinase, a key component of the IL-7R pathway, and trametinib inhibition of MEK, a downstream component of the RAS pathway. Combination therapy with ruxolitinib and trametinib resulted in the near elimination of the leukemia. This study demonstrates that these two oncogenes, which frequently occur in T-ALL, can drive leukemia and suggests targeting drugs to the pathways they activate.