Walters, D. K. et al. Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 10, 65-75

Howard Hughes Medical Institute, Portland, Oregon 97239, USA.
Cancer Cell (Impact Factor: 23.52). 08/2006; 10(1):65-75. DOI: 10.1016/j.ccr.2006.06.002
Source: PubMed


Tyrosine kinases are aberrantly activated in numerous malignancies, including acute myeloid leukemia (AML). To identify tyrosine kinases activated in AML, we developed a screening strategy that rapidly identifies tyrosine-phosphorylated proteins using mass spectrometry. This allowed the identification of an activating mutation (A572V) in the JAK3 pseudokinase domain in the acute megakaryoblastic leukemia (AMKL) cell line CMK. Subsequent analysis identified two additional JAK3 alleles, V722I and P132T, in AMKL patients. JAK3(A572V), JAK3(V722I), and JAK3(P132T) each transform Ba/F3 cells to factor-independent growth, and JAK3(A572V) confers features of megakaryoblastic leukemia in a murine model. These findings illustrate the biological importance of gain-of-function JAK3 mutations in leukemogenesis and demonstrate the utility of proteomic approaches to identifying clinically relevant mutations.

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    • "genetic alterations might be necessary for progression from TAM to AMKL (Ahmed et al, 2004). Although acquired mutations of TP53, JAK3, JAK2 or FLT3 have been found in patients with DS-AMKL, the incidence of those gene mutations was low, and TP53 and JAK3 gene mutations have been identified in both DS-AMKL and TAM (Malkin et al, 2000; Walters et al, 2006; De Vita et al, 2007; Kiyoi et al, 2007; Klusmann et al, 2007; Malinge et al, 2008). Mutations of GATA1, JAK2, FLT3, KIT, or MPL were also found in children with non-DS-AMKL (Malinge et al, 2008). "
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    ABSTRACT: While acute megakaryoblastic leukaemia (AMKL) occurs in children with (DS-AMKL) and without (paediatric non-DS-AMKL) Down syndrome, it can also affect adults without DS (adult non-DS-AMKL). We have analysed these subgroups of patients (11 children with DS-AMKL, 12 children and four adults with non-DS-AMKL) for the presence of molecular lesions, including mutations and chromosomal abnormalities studied by sequencing and single nucleotide polymorphism array-based karyotyping, respectively. In children, AMKL was associated with trisomy 21 (somatic in non-DS-AMKL), while numerical aberrations of chromosome 21 were only rarely associated with adult AMKL. DS-AMKL was also associated with recurrent somatic gains of 1q (4/11 DS-AMKL patients). In contrast to trisomy 21 and gains of 1q, other additional chromosomal lesions were evenly distributed between children and adults with AMKL. A mutational screen found GATA1 mutations in 11/12 DS-AMKL, but mutations were rare in paediatric non-DS-AMKL (1/12) and adult AMKL (0/4). JAK3 (1/11), JAK2 (1/11), and TP53 mutations (1/11) were found only in patients with DS-AMKL. ASXL1, IDH1/2, DNMT3A, RUNX1 and CBL mutations were not found in any of the patient group studied, while NRAS mutation was identified in two patients with paediatric non-DS-AMKL.
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