Mullighan, C. G. et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc. Natl Acad. Sci. USA 106, 9414-9418

Departments of Pathology and Biostatistics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2009; 106(23):9414-8. DOI: 10.1073/pnas.0811761106
Source: PubMed


Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease consisting of distinct clinical and biological subtypes that are characterized by specific chromosomal abnormalities or gene mutations. Mutation of genes encoding tyrosine kinases is uncommon in ALL, with the exception of Philadelphia chromosome-positive ALL, where the t(9,22)(q34;q11) translocation encodes the constitutively active BCR-ABL1 tyrosine kinase. We recently identified a poor prognostic subgroup of pediatric BCR-ABL1-negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1-positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Here, we report activating mutations in the Janus kinases JAK1 (n = 3), JAK2 (n = 16), and JAK3 (n = 1) in 20 (10.7%) of 187 BCR-ABL1-negative, high-risk pediatric ALL cases. The JAK1 and JAK2 mutations involved highly conserved residues in the kinase and pseudokinase domains and resulted in constitutive JAK-STAT activation and growth factor independence of Ba/F3-EpoR cells. The presence of JAK mutations was significantly associated with alteration of IKZF1 (70% of all JAK-mutated cases and 87.5% of cases with JAK2 mutations; P = 0.001) and deletion of CDKN2A/B (70% of all JAK-mutated cases and 68.9% of JAK2-mutated cases). The JAK-mutated cases had a gene expression signature similar to BCR-ABL1 pediatric ALL, and they had a poor outcome. These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL.

Download full-text


Available from: Charles G Mullighan
  • Source
    • "Mutations occur in about 10% of high-risk childhood B-ALL cases [73]. In the setting of BCR-ABL1-like B-ALL, JAK mutations are also associated with concomitant IKZF1 (Ikaros) and CDKN2A/B alterations, and correlate with worse outcomes [74,75]. JAK2 mutations are also associated with CRLF2 rearrangements (as described above), and are described in 60% of Down syndrome (Trisomy 21)-associated ALL [76,77]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In the pediatric population, B-acute lymphoblastic leukemia (B-ALL) is the most prevalent childhood hematological malignancy, as well as the leading cause of childhood cancer-related mortality. Advances in cytogenetics utilizing array-based technologies and next-generation sequencing (NGS) techniques have revealed exciting insights into the genetic basis of this disease, with the hopes of developing individualized treatment plans for affected children. In this comprehensive review, we discuss our current understanding of childhood (pediatric) B-ALL and highlight the most recent genetic advances and their therapeutic implications.
    Full-text · Article · Jun 2014
  • Source
    • "In all PAX5-ELN cases, except for one in which PAX5 exon 5 was fused to ELN sequences, the breakpoints in PAX5 occurred in intron 7 [2,4,8]. Also, the breakpoints in ELN are heterogeneous and PAX5 is fused to either exon 2 or exon 5 of ELN (Table 1) [2,4,8]. Consequently, the consensus PAX5-ELN fusion protein consists of the DNA-binding paired domain, the octapeptide, and the nuclear localization signal of PAX5, which are fused to almost the entire ELN protein without the signal peptide (Figure 2). "
    [Show abstract] [Hide abstract]
    ABSTRACT: B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by recurrent genetic alterations including chromosomal translocations. The transcription factor PAX5, which is pivotal for B-cell commitment and maintenance, is affected by rearrangements, which lead to the expression of in-frame fusion genes in about 2.5% of the cases. Using conventional cytogenetics, fluorescence in situ hybridization (FISH), and molecular methods, an additional case with a der(9)t(7;9)(q11.23;p13) resulting in the expression of a PAX5-ELN fusion gene was identified. Furthermore, a general review of leukemia harboring a t(7;9)(q11.2;p13) or der(9)t(7;9)(q11.2;p13), which occurs more often in children than in adults and shows a remarkably high male preponderance, is given. These cytogenetically highly similar translocations lead to the expression of one of three different in frame PAX5-fusions, namely with AUTS2 (7q11.22), ELN (7q11.23), or POM121 (7q11.23), which constitute the only currently known cluster of PAX5 partner genes. Our report underlines the recurrent involvement of PAX5 in different fusion genes resulting either from t(7;9)(q11.2;p13) or der(9)t(7;9)(q11.2;p13), which cannot be distinguished cytogenetically and whose discrimination requires molecular analysis.
    Full-text · Article · Feb 2014 · Molecular Cytogenetics
  • Source
    • "Super activation of JAK family was usually observed in hematologic diseases. Some JAK mutations were found in high-risk childhood acute lymphoblastic leukemia (ALL) [42]. Single mutation of JAK2 V617F,which represented constitutive tyrosine kinase activation, was associated with myeloproliferative disorders [43]–[46]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Signal abnormalities in human cells usually cause unexpected consequences for individual health. We focus on these kinds of events involved in JAK-STAT signal pathways, especially the ones triggered by aberrant activated STAT3, an oncoprotein which participates in essential processes of cell survival, growth and proliferation in many types of tumors, as well as immune diseases. By establishing a STAT3 signal based high-throughput drug screening system in human lung cancer A549 cells, we have screened a library from natural products which contained purified compounds from medicinal herbs. One compound, named Brevilin A, exhibited both strong STAT3 signal inhibition and STAT3 signal dependent cell growth inhibition. Further investigations revealed that Brevilin A not only inhibits STAT3 signaling but also STAT1 signaling for cytokines induced phosphorylation of STAT3 and STAT1 as well as the expression of their target genes. In addition, we found Brevilin A could attenuate the JAKs activity by blocking the JAKs tyrosine kinase domain JH1. The levels of cytokine induced phosphorylation of STATs and other substrates were dramatically reduced by treatment of Brevilin A. The roles of Brevilin A targeting on JAKs activity indicate that Brevilin A may not only be used as a STAT3 inhibitor but also a compound blocking other JAK-STAT hyperactivation. Thus, these findings provided a strong impetus for the development of selective JAK-STAT inhibitors and therapeutic drugs in order to improve survival of patients with hyperactivated JAKs and STATs.
    Full-text · Article · May 2013 · PLoS ONE
Show more