Shi S, Calhoun HC, Xia F, et al. JAK signaling globally counteracts heterochromatic gene silencing. Nat Genet 2006;38:1071-6.

The importance of JAK2 in erythropoiesis, specifically in erythropoietin/erythropoietin-receptor signaling and in modulation of receptor expression, has been highlighted after the seminal role of the JAK2 mutant in myeloproliferative disorders (JAK2V617F) was described. The JAK/STAT pathway is evolutionarily conserved and plays an important role in cell proliferation and organism development. In this paper, Shi et al. used a Drosophila melanogaster hematopoietic tumor model to show that the role of JAK/STAT in tumorogenesis is mediated by suppression of epigenetic gene silencing, suggesting yet a third possible mechanism of action for mutated JAK2. D. melanogaster possesses a single JAK, known as Hopscotch (hop), and a single STAT, which are similar to JAK2 and STAT5 in higher organisms. Interestingly, a hyperactive mutant of hop, known as Tumorous lethal (Tum-l), displays a leukemia-like phenotype with hematopoietic tumors manifested as blood cell aggregates in the body cavities of drosophila and globally disrupts heterochromatic gene silencing. Shi and collegues found that several enhancers of Tum-l encoded mutations in proteins involved in chromatin remodeling. These proteins, including HP1 (heterochromatin protein-1), Su(var)3-9 (suppressor of variegation methylating histone 3 at lys 9), and Rpd3 (a histone deacetylase) silence genes by stabilizing heterochromatin structures. The presence of the mutant HP1, Su(var)3-9, and Rpd3 failed to induce hematopoietic tumors by themselves, but their tumorogenesis was enhanced in the presence of hyperactive JAK Tum-1. Furthermore, the authors showed that hopTum-l (gain-of-function JAK) disrupts heterochromatin-induced gene silencing in genes that are not normally a target of the JAK/STAT pathway. These findings demonstrate that disruption of heterochromatic gene silencing is essential for JAK-induced increased cell proliferation and tumorogenesis. Finally, the authors showed that overexpression of HP1 in the hopTum-l flies prevents formation of hematopoietic tumors and counteracts the tumorogenesis of mutant JAK.

In the early 20th century, Emil Heitz studied chromatin structure under the microscope and discovered the presence of heterochromatin (condensed chromatin) and euchromatin (decondensed chromatin) in eukaryotes1 . Later, it was discovered that genes in euchromatin were actively transcribed while genes in the heterochromatin remained largely silenced. Chromatin structure is comprised of nucleosome units, each formed by DNA and histone proteins. The histone proteins in heterochromatin are heavily acetylated and demethylated, and, as a result, genes located in the heterochromatin area of chromosomes are less accessible to the transcription machinery of the cell2 . Deacetylation, mediated by histone deacetylase, and methylation by Su(var)3-9 with subsequent binding of HP1, play an important role in the stabilization of D. melanogaster heterochromatin structure and the silencing of genes. A similar array of enzymes and nuclear chromatin-binding proteins are involved in the epigenetic silencing of genes in higher eukaryotes, including humans. The findings of Shi et al., which identify a role for the JAK/STAT pathway in “global” reversal of heterochromatic gene silencing, are significant because they show a direct link between signaling events and gene expression. The tumorogenesis seen in the gain-of-function JAK mutant (hopTum-l) might be due to removal of the epigenetic silencing of tumor suppressor genes, a removal that could be reversed in D. melanogaster by overexpression of the heterochromatin stabilizing protein HP1. The existence of a similar mechanism in JAK2V617F-induced myeloproliferative disorders is a tantalizing possibility that demands further investigation. The work of Shi and colleagues might also explain the dominant inhibitory, regulatory role of wild-type JAK2 co-expressed with JAK2V617F in vitro (these cells lose the erythropoietin independence that is seen in cells transfected with JAK2V617F)3 . Perhaps, wild-type JAK2 signaling counteracts the epigenetic changes induced by JAK2V617F and reverses the phenotype of cells carrying both wild-type and mutant JAK2 back to normal. Further, the mutagenesis-promoting properties of hyperactive JAK such as JAK2V617F may explain the frequent mitotic crossover in PV (present in 30 percent of PV patients) resulting in uniparenteral disomy and a high rate of homozygosity for somatic JAK2V617F mutation4 .

1.
Heitz E. Das Heterochromatin der moose,[The heterochromatin in moss.] Jahrb Wiss Botanik 1928;69 762-818.
2.
Struhl K. Histone acetylation and transcriptional regulatory mechanisms. Gene Dev. 1998;12:599-606.
3.
James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythemia vera. Nature 2005;434:1144-8.
4.
Kralovics R, Guan Y, Prchal JT. Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Experimental Hematology 2002;30:229-236.

Competing Interests

Drs. Afshar-Kharghan and Prchal indicated no relevant conflicts of interest.