Ikaros dominant negative isoform (Ik6) induces IL-3-independent survival of murine pro-B lymphocytes by activating JAK-STAT and up-regulating Bcl-xl levels.
Ikaros is an essential regulator of lymphocyte differentiation. Mice transgenic for the Ikaros dominant negative (DN) mutation rapidly develop lymphoid malignancies. Various human leukemias have also been reported to express Ikaros DN isoforms, but its role in leukemogenesis is yet to be defined. We demonstrate that overexpressed Ikaros DN (Ik6) prolonged the survival of two different murine pro-B cell lines in cytokine deprived condition, and this was associated with increased expression of Bcl-xl. A survey of the upstream controller(s) of Bcl-xl expression revealed Ik6 overexpression enhanced the phosphorylation of JAK2 and STAT5. Interestingly, the Ik6 expressing cell lines showed reduced expression of B-cell differentiation surface marker CD45R (B220), which is also known as a JAK2 inhibitor. Although further evaluation with human clinical materials are required, these results propose a putative role of Ik6 in the development of B-lineage acute lymphoblastic leukemia, by activating the JAK2-STAT5 pathway and thus stimulating the production of Bcl-xl.
Kano
Gen
G
Department of Paediatrics, Kyoto Prefectural University of Medicine, Japan.
Morimoto
Akira
A
Takanashi
Mami
M
Hibi
Shigeyoshi
S
Sugimoto
Tohru
T
Inaba
Tohru
T
Yagi
Tomohito
T
Imashuku
Shinsaku
S
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000502:physiology*; D007377:Interleukin-3; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology*; D020033:Protein Isoforms / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D051020:bcl-X Protein / Q000096:biosynthesis*
D051017:Apoptosis Regulatory Proteins; C494812:Bcl2l1 protein, mouse; D007377:Interleukin-3; D020033:Protein Isoforms; D050799:STAT5 Transcription Factor; D051020:bcl-X Protein; D051740:Ikaros Transcription Factor; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2