title: Dysregulated RasGRP1 responds to cytokine receptor input in T cell leukemogenesis.
abstract: Enhanced signaling by the small guanosine triphosphatase Ras is common in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), but the underlying mechanisms are unclear. We identified the guanine nucleotide exchange factor RasGRP1 (Rasgrp1 in mice) as a Ras activator that contributes to leukemogenesis. We found increased RasGRP1 expression in many pediatric T-ALL patients, which is not observed in rare early T cell precursor T-ALL patients with KRAS and NRAS mutations, such as K-Ras(G12D). Leukemia screens in wild-type mice, but not in mice expressing the mutant K-Ras(G12D) that encodes a constitutively active Ras, yielded frequent retroviral insertions that led to increased Rasgrp1 expression. Rasgrp1 and oncogenic K-Ras(G12D) promoted T-ALL through distinct mechanisms. In K-Ras(G12D) T-ALLs, enhanced Ras activation had to be uncoupled from cell cycle arrest to promote cell proliferation. In mouse T-ALL cells with increased Rasgrp1 expression, we found that Rasgrp1 contributed to a previously uncharacterized cytokine receptor-activated Ras pathway that stimulated the proliferation of T-ALL cells in vivo, which was accompanied by dynamic patterns of activation of effector kinases downstream of Ras in individual T-ALLs. Reduction of Rasgrp1 abundance reduced cytokine-stimulated Ras signaling and decreased the proliferation of T-ALL in vivo. The position of RasGRP1 downstream of cytokine receptors as well as the different clinical outcomes that we observed as a function of RasGRP1 abundance make RasGRP1 an attractive future stratification marker for T-ALL.
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Hartzell
authors.forename: Olga
authors.initials: O
authors.lastname: Ksionda
authors.forename: Ed
authors.initials: E
authors.lastname: Lemmens
authors.forename: Kristen
authors.initials: K
authors.lastname: Coakley
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Monique
authors.initials: M
authors.lastname: Dail
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.forename: Christopher
authors.initials: C
authors.lastname: Govern
authors.forename: Jeroen
authors.initials: J
authors.lastname: Bakker
authors.forename: Tineke L
authors.initials: TL
authors.lastname: Lenstra
authors.forename: Kristin
authors.initials: K
authors.lastname: Ammon
authors.forename: Anne
authors.initials: A
authors.lastname: Boeter
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Winter
authors.forename: Mignon
authors.initials: M
authors.lastname: Loh
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.forename: Arup K
authors.initials: AK
authors.lastname: Chakraborty
authors.forename: Matthias
authors.initials: M
authors.lastname: Wabl
authors.forename: Jeroen P
authors.initials: JP
authors.lastname: Roose
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002648:Child; D017931:DNA Primers / Q000235:genetics; D004075:Diglycerides; D004789:Enzyme Activation / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D016254:Mutagenesis, Insertional; D009841:Oligonucleotides / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D004075:Diglycerides; D020662:Guanine Nucleotide Exchange Factors; D009841:Oligonucleotides; D034741:RNA, Small Interfering; C112278:Rasgrp1 protein, mouse; D018631:ras Proteins