Editors' ChoiceCancer

JAK and Jumonji: Deadly Playmates

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Science Translational Medicine  05 Jan 2011:
Vol. 3, Issue 64, pp. 64ec1
DOI: 10.1126/scitranslmed.3002071

It was the pathologist Thomas Hodgkin who first described lymphoma in 1932, yet 80 years later, researchers are still grappling with the complexity of these recalcitrant tumors. Lymphomas are now broadly classified as non-Hodgkin's or Hodgkin's based on their histological appearance. However, this classification is far from perfect— for example, a subtype of non-Hodgkin's lymphoma termed primary mediastinal B cell lymphoma (PMBL) shares many clinical features with Hodgkin's lymphomas, including the amplification of genes on chromosome 9p24. In a new study, Rui et al. used an RNA interference (RNAi) genetic screen to identify specific genes that are amplified on chromosome 9p24 and then showed how they cooperate to promote survival and progression of PMBL and Hodgkin's lymphomas.

The authors identified three candidate genes in their screen: the RANBP6 gene, which encodes a protein of unknown function; JMJD2C, which encodes a member of the Jumonji domain 2 family of histone demethylases (that promote gene transcription by derepressing chromatin); and JAK2, which encodes a kinase that phosphorylates tyrosine 41 on the tail of histone H3 leading to increased gene expression.

The authors found that PMBL tumor cells and Hodgkin's lymphomas harboring the 9p24 gene amplifications showed activation of JAK signaling and that blocking the expression of JAK2 by means of RNAi or chemical inhibitors reduced the viability of these cells by promoting apoptosis. Meanwhile, suppressing expression of JMJD2C through RNAi also reduced the viability of the tumor cells by slowing their progression through the cell cycle. And when both JAK2 and JMJD2C were inhibited, there was an even greater reduction in lymphoma cell survival and proliferation. In order to elucidate the reasons for these effects, the authors performed gene expression profiling after RNAi-mediated suppression of JMJD2C or JAK2. They found that inhibiting JMJD2C or JAK2 attenuated expression of the Myc oncogene by altering histone modifications at the Myc promoter, resulting in reduced expression of Myc target genes. These findings suggest that epigenetic modifications of the Myc promoter mediated by JMJD2C or JAK2 promote the growth of certain lymphomas.

Although we have made great progress in classifying and treating lymphomas since the time of Thomas Hodgkin, we still have much to learn. The next question is whether inhibitors that disrupt the function of JMJD2C can be developed and, if so, whether they will have additive effects when combined with JAK inhibitors, which are currently undergoing clinical testing.

L Rui et al., Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell 18, 590–605 (2010). [Abstract]

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