Loss‐of‐function JAK3 mutations in TMD and AMKL of Down syndrome

• Published in: British journal of haematology Vol. 137; no. 4; pp. 337 - 341
• Main Authors: De Vita, Serena, Mulligan, Claire, McElwaine, Suzanne, Dagna‐Bricarelli, Franca, Spinelli, Monica, Basso, Giuseppe, Nizetic, Dean, Groet, Jürgen
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2007; Blackwell
• Subjects: acute megakaryoblastic leukaemia; Base Sequence; Biological and medical sciences; Chromosome aberrations; Down syndrome; Down Syndrome - genetics; Down Syndrome - immunology; Enzyme Activation; Gene Deletion; Hematologic and hematopoietic diseases; Humans; Janus kinase 3; Janus Kinase 3 - genetics; Leukemia, Megakaryoblastic, Acute - complications; Leukemia, Megakaryoblastic, Acute - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical genetics; Medical sciences; Molecular Sequence Data; Mutation; myeloproliferative disorder; Protein-Tyrosine Kinases - genetics; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, DNA; tyrosine kinase; Chromosomal aberration; Trisomy; Hematology; Enzyme; Transferases; M7 acute myelocytic leukemia; tyrosine kinase; Chromosome G21; Acute leukemia; Aneuploidy; Hemopathy; Down syndrome; myeloproliferative disorder; Myeloproliferative syndrome; Janus kinase 3; acute megakaryoblastic leukaemia; Genetics; Mutation; Protein-tyrosine kinase
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2007.06574.x

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.