Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia

Hanna L M Rajala; Samuli Eldfors; Heikki Kuusanmäki; Arjan J van Adrichem; Thomas Olson; Sonja Lagström; Emma I Andersson; Andres Jerez; Michael J Clemente; Yiyi Yan; Dan Zhang; Andy Awwad; Pekka Ellonen; Olli Kallioniemi; Krister Wennerberg; Kimmo Porkka; Jaroslaw P Maciejewski; Thomas P Loughran; Caroline Heckman; Satu Mustjoki

doi:10.1182/blood-2012-12-474577

Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia

Hanna L M Rajala, Samuli Eldfors, Heikki Kuusanmäki, Arjan J van Adrichem, Thomas Olson, Sonja Lagström, Emma I Andersson, Andres Jerez, Michael J Clemente, Yiyi Yan, Dan Zhang, Andy Awwad, Pekka Ellonen, Olli Kallioniemi, Krister Wennerberg, Kimmo Porkka, Jaroslaw P Maciejewski, Thomas P Loughran, Caroline Heckman, Satu Mustjoki

172 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Blood
Vol/bind	121
Udgave nummer	22
Sider (fra-til)	4541-50
Antal sider	10
ISSN	0006-4971
DOI	https://doi.org/10.1182/blood-2012-12-474577
Status	Udgivet - 30 maj 2013
Udgivet eksternt	Ja

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10.1182/blood-2012-12-474577

http://www.bloodjournal.org/content/bloodjournal/121/22/4541.full.pdf

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Rajala, H. L. M., Eldfors, S., Kuusanmäki, H., van Adrichem, A. J., Olson, T., Lagström, S., Andersson, E. I., Jerez, A., Clemente, M. J., Yan, Y., Zhang, D., Awwad, A., Ellonen, P., Kallioniemi, O., Wennerberg, K., Porkka, K., Maciejewski, J. P., Loughran, T. P., Heckman, C., & Mustjoki, S. (2013). Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood, 121(22), 4541-50. https://doi.org/10.1182/blood-2012-12-474577

Rajala, HLM, Eldfors, S, Kuusanmäki, H, van Adrichem, AJ, Olson, T, Lagström, S, Andersson, EI, Jerez, A, Clemente, MJ, Yan, Y, Zhang, D, Awwad, A, Ellonen, P, Kallioniemi, O, Wennerberg, K, Porkka, K, Maciejewski, JP, Loughran, TP, Heckman, C & Mustjoki, S 2013, 'Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia', Blood, bind 121, nr. 22, s. 4541-50. https://doi.org/10.1182/blood-2012-12-474577

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title = "Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia",

abstract = "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.",

keywords = "Aged, Cohort Studies, Dimerization, Exome/genetics, Female, Genetic Testing, HeLa Cells, Humans, Leukemia, Large Granular Lymphocytic/genetics, Male, Middle Aged, Mutagenesis, Mutation, Phosphorylation/genetics, Protein Structure, Tertiary, STAT5 Transcription Factor/chemistry, Transcription, Genetic/genetics, Tumor Suppressor Proteins/genetics, src Homology Domains/genetics",

author = "Rajala, {Hanna L M} and Samuli Eldfors and Heikki Kuusanm{\"a}ki and {van Adrichem}, {Arjan J} and Thomas Olson and Sonja Lagstr{\"o}m and Andersson, {Emma I} and Andres Jerez and Clemente, {Michael J} and Yiyi Yan and Dan Zhang and Andy Awwad and Pekka Ellonen and Olli Kallioniemi and Krister Wennerberg and Kimmo Porkka and Maciejewski, {Jaroslaw P} and Loughran, {Thomas P} and Caroline Heckman and Satu Mustjoki",

year = "2013",

month = may,

day = "30",

doi = "10.1182/blood-2012-12-474577",

language = "English",

volume = "121",

pages = "4541--50",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

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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

SN - 0006-4971

VL - 121

SP - 4541

EP - 4550

JO - Blood

JF - Blood

IS - 22

ER -

Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia

Abstract

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