Cutting Edge: Codeletion of the Ras GTPase-Activating Proteins (RasGAPs) Neurofibromin 1 and p120 RasGAP in T Cells Results in the Development of T Cell Acute Lymphoblastic Leukemia

Abstract

Ras GTPase-activating proteins (RasGAPs) inhibit signal transduction initiated through the Ras small GTP-binding protein. However, which members of the RasGAP family act as negative regulators of T cell responses is not completely understood. Here, we investigated potential roles for the RasGAPs RASA1 and NF1 in T cells through the generation and analysis of T cell-specific RASA1 and NF1 double-deficient mice. In contrast to mice lacking either RasGAP alone in T cells, double-deficient mice developed T cell acute lymphoblastic leukemia/lymphoma (T-ALL). T-ALL originated at an early point in T cell development and was dependent upon activating mutations in the Notch1 gene. These findings highlight RASA1 and NF1 as co-tumor suppressors in the T cell lineage.

RASopathy Gene Mutations in Melanoma

“…Likewise, we identified two cases of NF1 -mutant melanomas, one with KRAS A146T and the other with KRAS Q22K , suggesting a similar situation. Our observation that RASA2 and NF1 significantly co-occur in melanoma (Krauthammer et al, 2015) is mirrored by a report that double-loss of NF1 and RASA1 in mice is required to enhance the development of T cell acute lymphoblastic leukemia/lymphoma, supporting a synergistic effect on dysregulation of RAS signaling (Lubeck et al, 2015). Similarly, our data showing co-occurring PTPN11 and NF1 mutations in melanoma (Krauthammer et al, 2015) is strengthened by a recent report of the presence of PTPN11 mutations in NF1 -mutant desmoplastic melanomas (Shain et al, 2015).…”

Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia

“…Moreover, RAS signaling is frequently hyperactivated in T-ALL patients [ 147 ], either by mutations in RAS itself [ 144 , 148 , 149 , 150 ] -especially in the early precursor subtype- [ 42 ] or by alterations in the activity or expression of other regulatory components of the pathway, mainly RAS GEFs (RAS guanidine nucleotide exchange factors) and RAS GAPs (RAS GTPase activating proteins). Indeed, neurofibromin 1 ( NF1 ), a tumor suppressor protein enhancing RAS hydrolyzing activity, was reported to be mutated in T-ALL patients [ 151 ], as well as to have a leukemogenic potential in vivo when deleted in combination with p120-RAS GAP in T-cells [ 152 ]. Another peculiar mechanism of increased RAS signaling in T-ALL results from the overexpression of RAS guanine nucleotide-releasing protein 1 (RASGRP1), a RAS GEF normally highly expressed in T-cells and critical for thymocyte differentiation and signal transduction downstream of the TCR [ 153 ].…”

RasGRP1 overexpression in T-ALL increases basal nucleotide exchange on Ras rendering the Ras/PI3K/Akt pathway responsive to protumorigenic cytokines

“…This idea is supported by studies showing that T-lineage knockouts of NF1 or p120RasGAP had only minor phenotype and did not result in T-ALL, 29,30 but that their combined deletion leads to the development of T-ALL. 31 The importance of RasGAPs is also highlighted by emerging data showing that NF1 is mutated in both pediatric and adult T-ALL patients. 32–34 Interestingly, there seems to be an increased instability of the Ras network evidenced by increased co-occurrence of NF1 mutations with other RasGAPs or RasGEFs in a wide range of human cancers.…”