Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis

Abstract

Ras guanyl nucleotide-releasing proteins (RasGRPs) are activators of Ras. Previous studies have indicated the possible involvement of RasGRP1 and RasGRP4 in leukemogenesis. Here, the predominant role of RasGRP1 in T-cell leukemogenesis is clarified. Notably, increased expression of RasGRP1, but not RasGRP4, was frequently observed in human T-cell malignancies. In a mouse bone marrow transplantation model, RasGRP1 exclusively induced T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) after a shorter latency when compared with RasGRP4. Accordingly, Ba/F3 cells transduced with RasGRP1 survived longer under growth factor withdrawal or phorbol ester stimulation than those transduced with RasGRP4, presumably due to the efficient activation of Ras. Intriguingly, NOTCH1 mutations resulting in a gain of function were found in 77% of the RasGRP1-mediated mouse T-ALL samples. In addition, gain-of-function NOTCH1 mutation was found in human T-cell malignancy with elevated expression of RasGRP1. Importantly, RasGRP1 and NOTCH1 signaling cooperated in the progression of T-ALL in the murine model. The leukemogenic advantage of RasGRP1 over RasGRP4 was attenuated by the disruption of a protein kinase C phosphorylation site (RasGRP1(Thr184)) not present on RasGRP4. In conclusion, cooperation between aberrant expression of RasGRP1, a strong activator of Ras, and secondary gain-of-function mutations of NOTCH1 have an important role in T-cell leukemogenesis.

Functional Redundancy of Sos1 and Sos2 for Lymphopoiesis and Organismal Homeostasis and Survival

“…Previous reports indicate that, as thymocyte maturation progresses, Sos involvement decays and RasGRP1 function becomes prevalent at the level of TCR-mediated signaling (8,14,16,33,34), although a recent study also reported functional cooperation between Sos1 and RasGRP1 during negative thymic selection (17). Consistently, our results showed that the cellular expansion taking place during the transition from DN to DP thymocytes was markedly reduced in Sos1/2 double-null mutants but not in mice lacking only one Sos isoform; such results support the notion of functional redundancy between Sos1 and Sos2 to sustain expansion of thymocytes occurring during progress through these maturation stages.…”

The role of wild type RAS isoforms in cancer

“…RASGRP1-overexpressing T-ALL exhibits constitutively high RAS-GTP, mechanistically distinguishing it from KRAS G12D -driven T-ALL that lacks constitutive GTP loading of RAS. Kitamura and colleagues showed that aberrantly expressed RASGRP1 cooperated with frequent secondary NOTCH1 gain-of-function mutations to promote mouse T-ALL [98]. …”

Gene expression profiling of murine T-cell lymphoblastic lymphoma identifies deregulation of S-phase initiating genes

“…Insertional mutagenesis in MLV infected mice has been widely used to study lymphoma biology, and several genes, that have since been associated with the development of human lymphomas, including Myc [15], Myb [16], D-type cyclines [17] and RasGrp1 [18] have been identified using these models. In this study, we aimed to identify new genes and pathways deregulated in murine T-LBL by performing integration analysis and gene expression profiling on tumors induced by the SL3-3 MLV.…”