In vivo leukemogenic potential of an interleukin 7 receptor α chain mutant in hematopoietic stem and progenitor cells

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 hetero...

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Published inBlood Vol. 122; no. 26; pp. 4259 - 4263
Main Authors Yokoyama, Kazuaki, Yokoyama, Nozomi, Izawa, Kiyoko, Kotani, Ai, Harashima, Akira, Hozumi, Katsuto, Tojo, Arinobu
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 19.12.2013
Subjects
Animals
Female
Fetus - physiology
Gene Expression Regulation, Neoplastic
Hematopoietic Stem Cells - physiology
Leukemia, B-Cell - genetics
Leukemia, B-Cell - pathology
Leukemia, T-Cell - genetics
Leukemia, T-Cell - pathology
Mice
Mice, Inbred BALB C
Mutagenesis, Insertional
Myeloproliferative Disorders - genetics
Myeloproliferative Disorders - pathology
Pregnancy
Receptor, Notch1 - genetics
Receptors, Interleukin-7 - genetics
Receptors, Interleukin-7 - metabolism
Stem Cells - physiology
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Summary: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. Key Points
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2012-08-451278