Uncovering the pathogenesis of large granular lymphocytic leukemia-novel STAT3 and STAT5b mutations.

Abstract:

:Large granular lymphocytic (LGL) leukemia is an incurable chronic disease, characterized by clonal expansion of cytotoxic T- or NK-cells in blood and bone marrow. Cytopenias (anemia, neutropenia) and autoimmune disorders such as rheumatoid arthritis are the most common clinical manifestations of LGL leukemia. Recently, somatic activating STAT3 gene mutations were shown to be specific for LGL leukemia with a prevalence of up to 70%. Analogous mutations in the STAT5b gene were seen in a smaller proportion of patients. These gain-of-function mutations are located in the SH2 domain of STAT3 and affect the phosphotyrosine-SH2 interaction required for dimerization of STAT3. The mutations increase the phosphorylation of STAT3 and STAT5b and enhance the transcriptional activity of the mutated proteins. STAT3 and STAT5b mutations can be used as molecular markers for LGL leukemia diagnostics, and they present novel therapeutic targets for STAT3 and STAT5b inhibitors, which currently are in development for treatment of cancer and autoimmune disorders.

journal_name

Ann Med

journal_title

Annals of medicine

authors

Rajala HL,Porkka K,Maciejewski JP,Loughran TP Jr,Mustjoki S

doi

10.3109/07853890.2014.882105

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

114-22

issue

3

eissn

0785-3890

issn

1365-2060

journal_volume

46

pub_type

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