Recurring mutations in myeloproliferative neoplasms alter epigenetic regulation of gene expression.
The prevalence of activating JAK2 mutations in myeloproliferative neoplasms (MPNs) suggests that aberrant gene expression due to deregulated signaling of the JAK2/STAT pathway plays an important role in the etiology of these diseases. While likely true, recent work has uncovered some fascinating new insights into both the function of mutationally-activated JAK2 as well as other mutated gene products in MPNs, and how these mutations may affect gene expression. In addition to being a cytoplasmic tyrosine kinase that relays signals from cytokine receptors, activated JAK2 can also function in the nucleus where it phosphorylates histones and deregulates binding of the transcriptional repressor HP1α. In addition, MPN-associated JAK2 mutants phosphorylate PRMT5 and inhibit its histone methyltransferase activity. Thus, in addition to the classical JAK/STAT pathway, JAK2 activating mutations in MPNs may deregulate gene expression by altering epigenetic mechanisms. Studies aimed at identifying the biochemical ramifications of other recurring MPN mutations also suggest deregulated epigenetic modifications may be important in MPN formation. Mutant TET2, as well as IDH1/2, impairs the hydroxylation of methylcytosine, thus affecting DNA methylation. Likewise, mutations in EZH2, a histone methyl transferase, ASXL1, which functions in chromatin modifier complexes, and the DNA methyltransferase DNMT3A, appear to inactivate the functions of these proteins toward regulating the epigenetic state of genes. Thus, it is likely that the control of gene expression by epigenetic mechanisms plays an important role in MPNs, since multiple recurring mutations in MPNs alter normal epigenetic regulatory mechanisms.
Department of Molecular Oncology, Moffitt Cancer Center and Research Institute USA.
Gary W
GW
Reuther