Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia
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Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. / Rajala, Hanna L M; Eldfors, Samuli; Kuusanmäki, Heikki; van Adrichem, Arjan J; Olson, Thomas; Lagström, Sonja; Andersson, Emma I; Jerez, Andres; Clemente, Michael J; Yan, Yiyi; Zhang, Dan; Awwad, Andy; Ellonen, Pekka; Kallioniemi, Olli; Wennerberg, Krister; Porkka, Kimmo; Maciejewski, Jaroslaw P; Loughran, Thomas P; Heckman, Caroline; Mustjoki, Satu.
I: Blood, Bind 121, Nr. 22, 30.05.2013, s. 4541-50.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia
AU - Rajala, Hanna L M
AU - Eldfors, Samuli
AU - Kuusanmäki, Heikki
AU - van Adrichem, Arjan J
AU - Olson, Thomas
AU - Lagström, Sonja
AU - Andersson, Emma I
AU - Jerez, Andres
AU - Clemente, Michael J
AU - Yan, Yiyi
AU - Zhang, Dan
AU - Awwad, Andy
AU - Ellonen, Pekka
AU - Kallioniemi, Olli
AU - Wennerberg, Krister
AU - Porkka, Kimmo
AU - Maciejewski, Jaroslaw P
AU - Loughran, Thomas P
AU - Heckman, Caroline
AU - Mustjoki, Satu
PY - 2013/5/30
Y1 - 2013/5/30
N2 - Large granular lymphocytic (LGL) leukemia is characterized by clonal expansion of cytotoxic T cells or natural killer cells. Recently, somatic mutations in the signal transducer and activator of transcription 3 (STAT3) gene were discovered in 28% to 40% of LGL leukemia patients. By exome and transcriptome sequencing of 2 STAT3 mutation-negative LGL leukemia patients, we identified a recurrent, somatic missense mutation (Y665F) in the Src-like homology 2 domain of the STAT5b gene. Targeted amplicon sequencing of 211 LGL leukemia patients revealed 2 additional patients with STAT5b mutations (N642H), resulting in a total frequency of 2% (4 of 211) of STAT5b mutations across all patients. The Y665F and N642H mutant constructs increased the transcriptional activity of STAT5 and tyrosine (Y694) phosphorylation, which was also observed in patient samples. The clinical course of the disease in patients with the N642H mutation was aggressive and fatal, clearly different from typical LGL leukemia with a relatively favorable outcome. This is the first time somatic STAT5 mutations are discovered in human cancer and further emphasizes the role of STAT family genes in the pathogenesis of LGL leukemia.
AB - Large granular lymphocytic (LGL) leukemia is characterized by clonal expansion of cytotoxic T cells or natural killer cells. Recently, somatic mutations in the signal transducer and activator of transcription 3 (STAT3) gene were discovered in 28% to 40% of LGL leukemia patients. By exome and transcriptome sequencing of 2 STAT3 mutation-negative LGL leukemia patients, we identified a recurrent, somatic missense mutation (Y665F) in the Src-like homology 2 domain of the STAT5b gene. Targeted amplicon sequencing of 211 LGL leukemia patients revealed 2 additional patients with STAT5b mutations (N642H), resulting in a total frequency of 2% (4 of 211) of STAT5b mutations across all patients. The Y665F and N642H mutant constructs increased the transcriptional activity of STAT5 and tyrosine (Y694) phosphorylation, which was also observed in patient samples. The clinical course of the disease in patients with the N642H mutation was aggressive and fatal, clearly different from typical LGL leukemia with a relatively favorable outcome. This is the first time somatic STAT5 mutations are discovered in human cancer and further emphasizes the role of STAT family genes in the pathogenesis of LGL leukemia.
KW - Aged
KW - Cohort Studies
KW - Dimerization
KW - Exome/genetics
KW - Female
KW - Genetic Testing
KW - HeLa Cells
KW - Humans
KW - Leukemia, Large Granular Lymphocytic/genetics
KW - Male
KW - Middle Aged
KW - Mutagenesis
KW - Mutation
KW - Phosphorylation/genetics
KW - Protein Structure, Tertiary
KW - STAT5 Transcription Factor/chemistry
KW - Transcription, Genetic/genetics
KW - Tumor Suppressor Proteins/genetics
KW - src Homology Domains/genetics
U2 - 10.1182/blood-2012-12-474577
DO - 10.1182/blood-2012-12-474577
M3 - Journal article
C2 - 23596048
VL - 121
SP - 4541
EP - 4550
JO - Blood
JF - Blood
SN - 0006-4971
IS - 22
ER -
ID: 199431746