Distinct oncogenic Ras signals characterized by profound differences in flux through the RasGDP/RasGTP cycle

Abstract

T cell acute lymphoblastic leukemia/lymphoma (T-ALL) is an aggressive bone marrow cancer in children and adults, and chemotherapy often fails for relapsing patients. Molecularly targeted therapy is hindered by heterogeneity in T-ALL and mechanistic details of the affected pathways in T-ALL are needed. Deregulation of Ras signals is common in T-ALL. Ras is genetically mutated to a constitutively active form in about 15% of all haematopoietic malignancies, but there is a range of other ways to augment signaling through the Ras pathway. Several groups including our own uncovered that RasGRP1 overexpression leads to T-ALL in mouse models and in pediatric T-ALL patients, and we reported that this Ras guanine nucleotide exchange factor, RasGRP1, cooperates with cytokines to drive leukemogenesis. In our recent study by Ksionda et al. we analyzed the molecular details of cytokine receptor-RasGRP1-Ras signals in T-ALL and compared these to signals from mutated Ras alleles, which yielded several surprising results. Examples are the striking differences in flux through the RasGDP/RasGTP cycle in distinct T-ALL or unexpected differences in wiring of the Ras signaling pathway between T-ALL and normal developing T cells, which we will discuss here.

Keywords: PI3K; Ras; RasGAP; RasGRP1; cancer; heterogeneity; leukemia; mouse models; patients; therapy.

Figure 1.

Schematic comparison of different oncogenic Ras signaling in Ras^MUT and RasGRP1-overexpressing T-ALL. Left: Leukemic cells with constitutively active Ras display high net levels of active RasGTP and very low nucleotide exchange rates due to the defective GTPase function of Ras. Middle: RasGRP1-overexpressing T-ALL show high levels of flux through the RasGDP/GTP cycle, yet low net levels of RasGTP, presumably due to the high compensatory activity of RasGAP family members. Right: After cytokine activation, RasGRP1-overexpressing T-ALL reveal elevated RasGTP levels and active downstream signaling, primarily through the PI3K-Akt pathway.