Faculty Collaboration Database

Nras Q61R/+ and Kras-/- cooperate to downregulate Rasgrp1 and promote lympho-myeloid leukemia in early T-cell precursors. Blood 2021 Jun 10;137(23):3259-3271

Date

01/30/2021

Pubmed ID

33512434

Pubmed Central ID

PMC8351901

DOI

10.1182/blood.2020009082

Scopus ID

2-s2.0-85107817855 (requires institutional sign-in at Scopus site)   5 Citations

Abstract

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is an aggressive subtype of T-cell ALL. Although genetic mutations hyperactivating cytokine receptor/Ras signaling are prevalent in ETP-ALL, it remains unknown how activated Ras signaling contributes to ETP-ALL. Here, we find that in addition to the frequent oncogenic RAS mutations, wild-type (WT) KRAS transcript level was significantly downregulated in human ETP-ALL cells. Similarly, loss of WT Kras in NrasQ61R/+ mice promoted hyperactivation of extracellular signal-regulated kinase (ERK) signaling, thymocyte hyperproliferation, and expansion of the ETP compartment. Kras-/-; NrasQ61R/+ mice developed early onset of T-cell malignancy that recapitulates many biological and molecular features of human ETP-ALL. Mechanistically, RNA-sequencing analysis and quantitative proteomics study identified that Rasgrp1, a Ras guanine nucleotide exchange factor, was greatly downregulated in mouse and human ETP-ALL. Unexpectedly, hyperactivated Nras/ERK signaling suppressed Rasgrp1 expression and reduced Rasgrp1 level led to increased ERK signaling, thereby establishing a positive feedback loop to augment Nras/ERK signaling and promote cell proliferation. Corroborating our cell line data, Rasgrp1 haploinsufficiency induced Rasgrp1 downregulation and increased phosphorylated ERK level and ETP expansion in NrasQ61R/+ mice. Our study identifies Rasgrp1 as a negative regulator of Ras/ERK signaling in oncogenic Nras-driven ETP-like leukemia.

Author List

Wen Z, Yun G, Hebert A, Kong G, Ranheim EA, Finn R, Rajagoplan A, Li S, Zhou Y, Yu M, Damnernsawad A, Roose JP, Coon JJ, Wen R, Wang D, Zhang J

Author

Demin Wang PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Substitution
Animals
Cell Proliferation
Down-Regulation
Gene Expression Regulation, Leukemic
Guanine Nucleotide Exchange Factors
Humans
MAP Kinase Signaling System
Mice
Mice, Knockout
Monomeric GTP-Binding Proteins
Mutation, Missense
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Proto-Oncogene Proteins p21(ras)