Malinge, S. et al. Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia. Blood 109, 2202-2204

Université Paris-Sud 11, Orsay, Île-de-France, France
Blood (Impact Factor: 10.45). 04/2007; 109(5):2202-4. DOI: 10.1182/blood-2006-09-045963
Source: PubMed


Activation of tyrosine kinase genes is a frequent event in human hematologic malignancies. Because gene activation could be associated with gene dysregulation, we attempted to screen for activating gene mutation based on high-level gene expression. We focused our study on the Janus kinase 2 (JAK2) gene in 90 cases of acute leukemia. This strategy led to the identification of a novel JAK2-acquired mutation in a patient with Down syndrome (DS) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This mutation involves a 5-amino acid deletion within the JH2 pseudokinase domain (JAK2DeltaIREED). Expression of JAK2DeltaIREED in Ba/F3 cells induced constitutive activation of the JAK-STAT pathway and growth factor-independent cell proliferation. These results highlight the JAK2 pseudokinase domain as an oncogenic hot spot and indicate that activation of the JAK-STAT pathway may contribute to lymphoid malignancies and hematologic disorders observed in children with DS.


Available from: Raouf Ben Abdelali, Sep 29, 2015
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    • "A different mutation in JAK2 gene in a patient with Down syndrome associated precursor B-cell lymphoblastic leukemia was reported by Malinge et al., This mutation was in-frame deletion of five-amino acid residues from position 682 to 686, named as IREED mutation, in the pseudokinase domain of JAK2. This IREED mutant remains constitutively active and induces cytokine independence in Ba/F3 cells [43]. "
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    ABSTRACT: JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical role in transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune regulation, fertility, lactation, growth and embryogenesis. JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Negative regulators of JAK-STAT pathways include tyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of activated STATs (PIAS), suppressors of cytokine signaling (SOCS) proteins, and cytokine-inducible SH2-containing protein (CIS). Dysregulation of JAK-STAT pathway have been found to be key events in a variety of hematological malignancies. JAK inhibitors are among the first successful agents reaching clinical application. Ruxolitinib (Jakafi), a non-selective inhibitor of JAK1 & 2, has been approved by FDA for patients with intermediate to high risk primary or secondary myelofibrosis. This review will also summarize early data on selective JAK inhibitors, including SAR302503 (TG101348), lestaurtinib (CEP701), CYT387, SB1518 (pacritinib), LY2784544, XL019, BMS-911543, NS-018, and AZD1480.
    01/2013; 1(1):5. DOI:10.1186/2050-7771-1-5
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    • "The development of TMD and AMKL is almost always associated with stereotypical mutations in exon 2 of the GATA binding protein 1 (GATA1) gene resulting in the synthesis of a truncated GATA1 protein termed GATA1s[6],[122],[123]. Mutations in Janus kinase 3 (JAK3) have also been reported by several groups to be associated with AMKL[119],[124]–[128]. Additionally, one fifth of DS-ALL cases have been associated with janus kinase 2 (JAK2) point mutations[129],[130]. DS-ALL is also associated with aberrant expression of cyto kine receptor-like factor 2 (CRLF2) linked to genomic rearrangements[130]–[132]. Trisomy of an Hsa21-encoded gene, v-ets erythroblastosis virus E26 oncogene homolog (ERG), is required for development of the myeloproliferation defect in the Ts65Dn model[133]. "
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    ABSTRACT: Chromosome copy number aberrations, anueploidies, are common in the human population but generally lethal. However, trisomy of human chromosome 21 is compatible with life and people born with this form of aneuploidy manifest the features of Down syndrome, named after Langdon Down who was a 19(th) century British physician who first described a group of people with this disorder. Down syndrome includes learning and memory deficits in all cases, as well as many other features which vary in penetrance and expressivity in different people. While Down syndrome clearly has a genetic cause - the extra dose of genes on chromosome 21 - we do not know which genes are important for which aspects of the syndrome, which biochemical pathways are disrupted, or, generally how design therapies to ameliorate the effects of these disruptions. Recently, with new insights gained from studying mouse models of Down syndrome, specific genes and pathways are being shown to be involved in the pathogenesis of the disorder. This is opening the way for exciting new studies of potential therapeutics for aspects of Down syndrome, particularly the learning and memory deficits.
    03/2010; 24(2):87-99. DOI:10.1016/S1674-8301(10)60016-4
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    • "E627E 1 BCR/ABL-negative MPS: 1 Het: 1 0/1/0/0 [14] DIREED 1 B cell precursor ALL: 1 Het: 1 0/1/0/0 [15] "
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    ABSTRACT: The acquired Janus kinase 2 (JAK2) V617F mutation shows a high frequency in diverse BCR/ABL-negative chronic myeloproliferative disorders (CMPD), and it is typically associated with polycythemia vera (PV). The frequency of JAK2 V617F mutation is about 90% in patients with PV, 50-60% in patients with essential thrombocythemia (ET), primary myelofibrosis (PMF), and less in patients with other myeloid neoplasms, while extremely rare in lymphoid malignancies. About 20 kinds of novel mutations of JAK2 other than V617F have been reported recently in the literature. Among these mutations, only one case of JAK2 V617F/C618R has been reported in a 67-year-old patient with PV. Here, we report a rare case of JAK2 V617F/C618R in a 41-year-old Korean male patient with review of the relevant literature on JAK2 mutations other than V617F. Although the frequency of JAK2 mutations other than the V617F is very low, this study emphasizes the need for assiduous analysis of the JAK2 gene to characterize new mutations, to determine their frequency, and to improve understanding of the clinical phenotypes as well as prognostic and biologic features associated with these mutations.
    Cancer genetics and cytogenetics 03/2009; 189(1):43-7. DOI:10.1016/j.cancergencyto.2008.09.010 · 1.93 Impact Factor
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