Mutation in the RNA binding protein TIS11D/ZFP36L2 is associated with the pathogenesis of acute leukemia.
TIS11D is an AU-rich element binding protein that is involved in RNA metabolism and definitive hematopoiesis. Although disruption of genes related to hematopoiesis often leads to the development of leukemia and lymphoma, the involvement of TIS11D in hematological malignancies remains to be determined. In the present study, we identified a heterozygous frameshift mutation (I373fsX91) in the carboxy-terminus of the TIS11D gene in leukemic cells from a patient with acute myeloid leukemia. Moreover, biallelic inactivation of the TIS11D gene resulting from a hemizygous frameshift mutation (G107fsX80) was identified in the Burkitt's lymphoma cell line DG75. In HeLa cells, overexpression of wild-type TIS11D protein (TIS11D(WT)) induced growth inhibition and an S phase checkpoint response, while the mutant protein (TIS11D(I373fsX91)) showed a diminished effect. Interestingly, this response was accompanied by p21 downregulation, which is frequently seen in the cellular response to ultraviolet irradiation. These data suggest that the dysregulation of TIS11D function is associated with the pathogenesis of certain types of leukemia.
Department of Hematology, Kumamoto University Graduate School of Biosciences, Kumamoto, Japan. sakusaku6554@fc.kuh.kumamoto-u.ac.jp
Eisaku
E
Iwanaga
Tomoko
T
Nanri
Hiroaki
H
Mitsuya
Norio
N
Asou
D000818:Animals; D002051:Burkitt Lymphoma / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D016368:Frameshift Mutation; D016158:Genes, p53; D006367:HeLa Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016601:RNA-Binding Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
D016601:RNA-Binding Proteins; D014157:Transcription Factors; C091750:ZFP36L2 protein, human