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Loss‐of‐function JAK3 mutations in TMD and AMKL of Down syndrome
Author(s) -
De Vita Serena,
Mulligan Claire,
McElwaine Suzanne,
DagnaBricarelli Franca,
Spinelli Monica,
Basso Giuseppe,
Nizetic Dean,
Groet Jürgen
Publication year - 2007
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2007.06574.x
Subject(s) - acute megakaryoblastic leukemia , mutation , down syndrome , janus kinase 3 , pathogenesis , medicine , genetics , immunology , biology , gene , immune system , interleukin 21 , t cell
Summary Acquired mutations activating Janus kinase 3 (jak3) have been reported in Down syndrome (DS) and non‐DS patients with acute megakaryoblastic leukaemia (AMKL). This highlighted jak3‐activation as an important event in the pathogenesis of AMKL, and predicted inhibitors of jak3 as conceptual therapeutics for AMKL. Of 16 DS‐transient myeloproliferative disorder (TMD)/AMKL patients tested, seven showed JAK3 mutations. Three mutations deleted the kinase (JH1) domain, abolishing the main function of jak3. Another patient displayed a mutation identical to a previously reported inherited loss‐of‐function causing severe combined immunodeficiency. Our data suggest that both gain‐, and loss‐of function mutations of jak3 can be acquired in DS‐TMD/AMKL.