title: In vivo leukemogenic potential of an interleukin 7 receptor α chain mutant in hematopoietic stem and progenitor cells.
abstract: Somatic gain-of-function mutations in interleukin 7 receptor α chain (IL7Rα) have been described in pediatric T and B acute lymphoblastic leukemias (T/B-ALLs). Most of these mutations are in-frame insertions in the extracellular juxtamembrane-transmembrane region. By using a similar mutant, a heterozygous in-frame transmembrane insertional mutation (INS), we validated leukemogenic potential in murine hematopoietic stem/progenitor cells, using a syngeneic transplantation model. We found that ectopic expression of INS alone in hematopoietic stem/progenitor cells caused myeloproliferative disorders, whereas expression of INS in combination with a Notch1 mutant led to the development of much more aggressive T-ALL than with wild-type IL7Rα. Furthermore, forced expression of INS in common lymphoid progenitors led to the development of mature B-cell ALL/lymphoma. These results demonstrated that INS has significant in vivo leukemogenic activity and that the lineage of the resulting leukemia depends on the developmental stage in which INS occurs, and/or concurrent mutations.
authors.affiliation: Division of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan;
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Nozomi
authors.initials: N
authors.lastname: Yokoyama
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Izawa
authors.forename: Ai
authors.initials: A
authors.lastname: Kotani
authors.forename: Akira
authors.initials: A
authors.lastname: Harashima
authors.forename: Katsuto
authors.initials: K
authors.lastname: Hozumi
authors.forename: Arinobu
authors.initials: A
authors.lastname: Tojo
mesh_terms: D000818:Animals; D005260:Female; D005333:Fetus / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D015448:Leukemia, B-Cell / Q000235:genetics* / Q000473:pathology; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016254:Mutagenesis, Insertional; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000473:pathology; D011247:Pregnancy; D051881:Receptor, Notch1 / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain