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Br J Haematol. 2007 May;137(4):337-41.

Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome.

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  • 1Centre for Haematology, Institute of Cell and Molecular Science, Barts & The London, Queen Mary's School of Medicine, University of London, London, UK.


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.

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