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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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. Key Points
AbstractList 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
Key Points Gain-of function mutation of IL7Rα induces lymphoid leukemia as well as myeloproliferative disease. In vivo oncogenicity of mutant IL7Rα is influenced by the differentiation stage at which it occurs.
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.
Author Izawa, Kiyoko
Yokoyama, Nozomi
Hozumi, Katsuto
Tojo, Arinobu
Yokoyama, Kazuaki
Harashima, Akira
Kotani, Ai
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Snippet 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)....
Key Points Gain-of function mutation of IL7Rα induces lymphoid leukemia as well as myeloproliferative disease. In vivo oncogenicity of mutant IL7Rα is...
SourceID crossref
pubmed
elsevier
SourceType Aggregation Database
Index Database
Publisher
StartPage 4259
SubjectTerms 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
Title In vivo leukemogenic potential of an interleukin 7 receptor α chain mutant in hematopoietic stem and progenitor cells
URI https://dx.doi.org/10.1182/blood-2012-08-451278
https://www.ncbi.nlm.nih.gov/pubmed/24174626
Volume 122
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