Article

JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA

Departments of Pathology and Biostatistics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 07/2009; 106(23):9414-8. DOI: 10.1073/pnas.0811761106
Source: PubMed

ABSTRACT 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.

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    • "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]. "
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    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.
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    • "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). "
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    • "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]. "
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