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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2499.
JAK2: how many faces in MPDs?UNIVERSITY OF FLORENCE
In this issue of Blood, Pardanani and colleagues provide evidence that single nucleotide polymorphisms (SNPs) in JAK2 contribute to the phenotypic pleiotropy of chronic myeloproliferative disorders (MPDs).
SNPs are the most frequently occurring genetic variation in the human genome, estimated to exceed 9 million bases, and contribute to heritable interindividual differences in complex phenotypes. Development of high-throughput genotyping methods has expanded their use to include identification of genomic regions contributing to cancer phenotype.2 Pardanani and colleagues have used an association-based study design to compare allele frequency at polymorphic loci in candidate genes involved in the JAK-STAT signaling pathway in MPD patients. They found that 3 polymorphic alleles in the JAK2 gene itself were differentially represented in patients with PV or ET, while 3 additional SNPs were associated with PV only. Of note, association of the 3 SNPs with PV or ET remained after stratifying for JAK2V617F mutational status. Conversely, genotyping of other candidate genes—EPOR, MPL, and GCSFR—did not produce additional informative SNPs. What are the implications of these findings, and where can they lead? First, they provide a proof-of-principle that genetic variations other than the V617F allele contribute to phenotypic diversity in MPDs, although those SNPs do not necessarily represent disease-predisposing alleles. Due to an anticipated relatively small effect of modifier allele(s) in complex phenotypes, multiple testing corrections are necessary to account for the coincidental concurrence of other individual genetic variables, themselves acting as modifiers.3 The recent founding of international collaborative groups focused on MPDs represents an ideal platform for these kinds of studies, including replication of current findings in an independent patient set. Second, researchers are urged to come back to JAK2 to study functional correlates of the SNPs characterized by Pardanani and colleagues. When SNPs do occur, they could result in abnormal expression, stability, or function of a protein, and directly contribute to phenotypic variations. The task is now to assess whether and how these SNPs in JAK2 influence cellular functions,4 providing a rationale for their preferential association with unique MPD phenotypes. The coexistence of a catalytic and a negative autoregulatory domain in the same mol-ecule originally led to the acronym JAK2: Janus Kinase 2, in reference to the Roman God Janus who is depicted with 2 faces to signify beginnings and endings. Playfully, someone also referred to JAK2 as simply as "Just Another Kinase."5 But findings from the work of Pardanani and colleagues suggest that 2 faces are still not enough to decipher the whole story of JAK2 in MPDs.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
