Expression analysis and characterization of alternatively spliced transcripts of human IL-7Ralpha chain encoding two truncated receptor proteins in relapsed childhood all.
In the family of cytokines and cytokine receptors, alternative splicing of pre-mRNA is a frequently observed process that generates different protein isoforms from a single genetic locus. The splicing-derived cytokine receptor protein isoforms are mostly soluble receptors or show alterations in their cytoplasmic domain. It is possible that receptor abnormalities or a pathological ratio of different isoforms may contribute to leukaemia by circumventing normal growth factor control or altering the balance of proliferation and differentiation. IL-7 plays a critical role in early stages of both B and T cell maturation. Moreover, it stimulates the expansion of mature T cells including anti-tumour reactive cells as well as a number of T and B cell malignancies underlining its potential importance for deregulated lymphoid proliferation and leukaemogenesis. Here, we present detailed data on the expression of the interleukin 7 receptor alpha chain (IL-7Ralpha) in leukaemic cells from 210 children with acute lymphoblastic leukaemia (ALL) and describe two novel alternatively spliced transcripts of human IL-7Ralpha coding for truncated receptor proteins which are still capable of binding IL-7. IL-7Ralpha mRNA expression was more frequent in more mature pre-B ALL [91% (30/33)] than in common [81% (81/100)] or pro-B ALL [64% (18/28)], or even in T ALL [64% (29/45)]. These results are in concordance with flow cytometric analyses on the proportion of IL-7Ralpha bearing cells among total blast cell population. Our results lead us to assume that splicing derived IL-7Ralpha isoforms play a potential role in modulating IL-7 signal transduction and might be important for the pathogenesis of leukaemia.
Korte
A
A
Department of Pediatric Oncology/Hematology, Charité Medical Center, Campus Virchow, Germany. alexander.korte@charite.de
Köchling
J
J
Badiali
L
L
Eckert
C
C
Andreae
J
J
Geilen
W
W
Kebelmann-Betzing
C
C
Taube
T
T
Wu
S
S
Henze
G
G
Seeger
K
K
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002648:Child; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D005091:Exons; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007438:Introns; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism*; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D020033:Protein Isoforms; D012333:RNA, Messenger; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain