Mutations that collaborate with IL-7Ra signaling pathways to drive ALL

Gisele O L Rodrigues; Sarah D Cramer; Hila Y Winer; Julie A Hixon; WenQing Li; José Andres Yunes; Scott K Durum

doi:10.1016/j.jbior.2021.100788

Mutations that collaborate with IL-7Ra signaling pathways to drive ALL

Adv Biol Regul. 2021 May:80:100788. doi: 10.1016/j.jbior.2021.100788. Epub 2021 Jan 21.

Authors

Gisele O L Rodrigues¹, Sarah D Cramer², Hila Y Winer³, Julie A Hixon³, WenQing Li³, José Andres Yunes⁴, Scott K Durum⁵

Affiliations

¹ Cytokines and Immunity Section, Laboratory of Cancer Immunometabolism, National Cancer Institute, National Institutes of Health (NIH), Frederick, MD, USA; Molecular Biology Laboratory, Boldrini Children's Center, Campinas, Brazil; Department of Genetics, Evolution and Bioagents, Institute of Biology, State University of Campinas (UNICAMP), Campinas, Brazil.
² Cytokines and Immunity Section, Laboratory of Cancer Immunometabolism, National Cancer Institute, National Institutes of Health (NIH), Frederick, MD, USA; Comparative Biomedical Scientist Training Program, NIH, Bethesda, MD, USA; Department of Veterinary Medicine, University of Maryland, College Park, MD, USA.
³ Cytokines and Immunity Section, Laboratory of Cancer Immunometabolism, National Cancer Institute, National Institutes of Health (NIH), Frederick, MD, USA.
⁴ Department of Genetics, Evolution and Bioagents, Institute of Biology, State University of Campinas (UNICAMP), Campinas, Brazil.
⁵ Cytokines and Immunity Section, Laboratory of Cancer Immunometabolism, National Cancer Institute, National Institutes of Health (NIH), Frederick, MD, USA. Electronic address: durums@mail.nih.gov.

PMID: 33578108
DOI: 10.1016/j.jbior.2021.100788

Abstract

The IL-7 pathway is required for normal T cell development and survival. In recent years the pathway has been shown to be a major driver of acute lymphoblastic leukemia (ALL), the most common cancer in children. Gain-of-function mutations in the alpha chain of the IL-7 receptor found in ALL patients clearly demonstrated that this pathway was a driver. However mutant IL-7R alone was insufficient to transform primary T cell progenitors, indicating that cooperating mutations were required. Here we review evidence for additional oncogenic mutations in the IL-7 pathway. We discuss several oncogenes, loss of tumor suppressor genes and epigenetic effects that can cooperate with mutant IL-7 receptor. These include NRas, HOXA, TLX3, Notch 1, Arf, PHF6, WT1, PRC, PTPN2 and CK2. As new therapeutics targeting the IL-7 pathway are developed, combination with agents directed to cooperating pathways offer hope for novel therapies for ALL.

Keywords: Acute lymphoblastic leukemia; IL7R; Leukemia; Mutation.

Publication types

Research Support, N.I.H., Extramural
Review

MeSH terms

Casein Kinase II / genetics
Casein Kinase II / metabolism
Child
Epigenesis, Genetic
GTP Phosphohydrolases / genetics
GTP Phosphohydrolases / metabolism
Gene Expression Regulation, Leukemic*
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Interleukin-7 / genetics*
Interleukin-7 / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mutation*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
Protein Tyrosine Phosphatase, Non-Receptor Type 2 / genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism
Receptor, Notch1 / genetics
Receptor, Notch1 / metabolism
Receptors, Interleukin-7 / genetics*
Receptors, Interleukin-7 / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Signal Transduction / genetics*
T-Lymphocytes / metabolism
T-Lymphocytes / pathology
Transcription Factors / genetics
Transcription Factors / metabolism
WT1 Proteins / genetics
WT1 Proteins / metabolism

Substances

Homeodomain Proteins
IL7 protein, human
Interleukin-7
Membrane Proteins
NOTCH1 protein, human
PHF6 protein, human
Receptor, Notch1
Receptors, Interleukin-7
Repressor Proteins
TLX3 protein, human
Transcription Factors
WT1 Proteins
WT1 protein, human
interleukin-7 receptor, alpha chain
peroxisome-proliferator-activated receptor-gamma coactivator-1
HoxA protein
Casein Kinase II
PTPN2 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 2
GTP Phosphohydrolases
NRAS protein, human