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

Mues, Marsilius; Roose, Jeroen P.

doi:10.1080/21541248.2016.1187323

Cited by 10 publications

(7 citation statements)

References 54 publications

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“…Cytokines can trigger RAS activation and RASGTP transmits signals to downstream effector kinase pathways, such as the RAF-MEK-ERK, Phosphatidylinositol 3-kinase (PI3K)-AKT and mTORC1-S6 and mTORC2-AKT pathways 4 , 20 , 30 , 31 . In T-ALL cell lines, KRAS G12D causes high baseline RASGTP levels 4 , 32 , whereas overexpressed RASGRP1 constitutively loads RAS with GTP and RASGTP is constantly hydrolyzed back to inactive RASGDP 4 ( Figure 1D ). Kras G12D in hematopoietic cells leads to elevated RASGTP levels at baseline 11 , 15 , whereas increases in RASGTP are more modest for Nras G12D 15 .…”

Section: Resultsmentioning

confidence: 99%

Increased baseline RASGRP1 signals enhance stem cell fitness during native hematopoiesis

et al. 2020

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Oncogenic mutations in RAS genes, like KRAS G12D or NRAS G12D , trap Ras in the active state and cause myeloproliferative disorder and T cell leukemia (T-ALL) when induced in the bone marrow via Mx1CRE. The RAS exchange factor RASGRP1 is frequently overexpressed in T-ALL patients. In T-ALL cell lines overexpression of RASGRP1 increases flux through the RASGTP/RasGDP cycle. Here we expanded RASGRP1 expression surveys in pediatric T-ALL and generated a RoLoRiG mouse model crossed to Mx1CRE to determine the consequences of induced RASGRP1 overexpression in primary hematopoietic cells. RASGRP1-overexpressing, GFP-positive cells outcompeted wild type cells and dominated the peripheral blood compartment over time. RASGRP1 overexpression bestows gain-of-function colony formation properties to bone marrow progenitors in medium containing limited growth factors. RASGRP1 overexpression enhances baseline mTOR-S6 signaling in the bone marrow, but not in vitro cytokine-induced signals.In agreement with these mechanistic findings, hRASGRP1-ires-EGFP enhances fitness of stem-and progenitor-cells, but only in the context of native hematopoiesis. RASGRP1 overexpression is distinct from KRAS G12D or NRAS G12D , does not cause acute leukemia on its own, and leukemia virus insertion frequencies predict that RASGRP1 overexpression can effectively cooperate with lesions in many other genes to cause acute T cell leukemia.

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Section: Resultsmentioning

confidence: 99%

Increased baseline RASGRP1 signals enhance stem cell fitness during native hematopoiesis

et al. 2020

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“…In murine T-ALL cells with increased RASGRP1 expression, RASGRP1 contributed to cytokine receptor-activated RAS pathway that stimulated the proliferation of T-ALL cells in vivo [ 75 ]. Remarkably, RASGRP1 overexpression in T-ALL cells seems to impinge primarily on PI3K/Akt rather than on MEK/ERK signaling [ 79 , 80 ].…”

Section: Activation Of Mtorc1 and Mtorc2 In T-all Cellsmentioning

confidence: 99%

Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update

Evangelisti

Chiarini

McCubrey

et al. 2018

IJMS

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignancy that arises from the clonal expansion of transformed T-cell precursors. Although T-ALL prognosis has significantly improved due to the development of intensive chemotherapeutic protocols, primary drug-resistant and relapsed patients still display a dismal outcome. In addition, lifelong irreversible late effects from conventional therapy are a growing problem for leukemia survivors. Therefore, novel targeted therapies are required to improve the prognosis of high-risk patients. The mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct multiprotein complexes, which are referred to as mTOR complex 1 (mTORC1) and mTORC2. These two complexes regulate a variety of physiological cellular processes including protein, lipid, and nucleotide synthesis, as well as autophagy in response to external cues. However, mTOR activity is frequently deregulated in cancer, where it plays a key oncogenetic role driving tumor cell proliferation, survival, metabolic transformation, and metastatic potential. Promising preclinical studies using mTOR inhibitors have demonstrated efficacy in many human cancer types, including T-ALL. Here, we highlight our current knowledge of mTOR signaling and inhibitors in T-ALL, with an emphasis on emerging evidence of the superior efficacy of combinations consisting of mTOR inhibitors and either traditional or targeted therapeutics.

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“…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 ]. In T-ALL, RASGRP1 induces higher rates of GTP/GDP exchange and promotes cytokine-induced RAS downstream signaling, mainly via the PI3K/AKT axis [ 154 , 155 ]. Moreover, loss-of-function mutations in PTPN11 , encoding the protein phosphatase non-receptor type 11, which negatively regulates the RAS pathway, have also been described [ 156 ].…”

Section: Signaling Pathways Involved In the Development Of T-allmentioning

confidence: 99%

Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia

Bongiovanni

Saccomani

Piovan

2017

IJMS

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and diffusion to the central nervous system. In the past decade, the genomic landscape of T-ALL has been the target of intense research. The identification of specific genomic alterations has contributed to identify strong oncogenic drivers and signaling pathways regulating leukemia growth. Notwithstanding, T-ALL patients are still treated with high-dose multiagent chemotherapy, potentially exposing these patients to considerable acute and long-term side effects. This review summarizes recent advances in our understanding of the signaling pathways relevant for the pathogenesis of T-ALL and the opportunities offered for targeted therapy.

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

Cited by 10 publications

References 54 publications

Increased baseline RASGRP1 signals enhance stem cell fitness during native hematopoiesis

Increased baseline RASGRP1 signals enhance stem cell fitness during native hematopoiesis

Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update

Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia

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