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Histone Signature Leads to Gene Mutation in Pediatric Leukemia

NEW YORK (GenomeWeb News) – A study appearing online yesterday in Nature Genetics has unearthed a gene mutation that appears to upend typical chromatin patterns in some cases of pediatric acute lymphoblastic leukemia.

Starting from a mass spectrometry-based analysis of histone protein patterns in more than 100 lines from the Cancer Cell Line Encyclopedia, researchers from the US and China detected six cancer-associated histone methylation signatures. These included a signature marked by a jump in histone 3 lysine 36, or H3K36 dimethylation levels — identified in tumors containing translocations that bump up expression of the methyltransferase enzyme-coding gene called NSD2.

But it turned up in some other lines too, prompting scrutiny of NSD2 sequences in those translocation-free tumor lines. In particular, the team's analysis of ALL lines with the H3K36 signature revealed a point mutation in NSD2 that the team subsequently linked to such histone changes and increased cellular invasiveness. Mutations in NSD2 also turned up in a subset of leukemia samples from a much larger childhood cancer set.

"This study demonstrates the potential utility of chromatin profiling to functionally annotate gene mutations whose epigenetic consequences remain unknown," Dana-Farber Cancer Institute researcher Levi Garraway and the Novartis Institutes for Biomedical Research's Frank Stegmeier, co-senior authors on the study, and their colleagues wrote.

"The recognition that NSD2 mutations produce a characteristic chromatin signature and dependency on oncogenic NSD2 activity suggests that this mutant protein may provide a therapeutic target in pediatric ALL," they noted, adding that such chromatin signatures may ultimately prove useful as biomarkers for tracking and predicting response to epigenetics-focused treatments.

Using a newly developed targeted mass spec-based global chromatin modification profiling method, researchers assessed 42 different histone H3 modification combinations in 115 lines from the Cancer Cell Line Encyclopedia — a genomically characterized cell line set that Garraway and colleagues introduced in Nature last spring.

Many of the cell lines selected from the CCLE had been generated from hematological cancers, the study's authors noted, a group of cancers in which epigenetic problems have been described previously.

The initial mass spec screen uncovered half a dozen chromatin signature clusters within the cancer lines, including a chromatin signature marked by much higher-than-usual levels of dimethylation at the histone H3K36 and a dip in representation from unmodified forms of the chromatin mark.

The H3K36 dimethylation signature was frequently found in multiple myeloma cell lines and cell lines from other tumors known to contain a translocation that dials up expression of the methyltransferase gene NSD2.

Investigators also saw the same sort of boost in H3K36 dimethylation levels in ALL lines lacking the NSD2 translocation. By bringing in sequence, expression, and copy number information on cell lines from the chromatin cluster, they determined that ALL lines harboring the telltale histone pattern also contained a point mutation within NSD2.

The group's subsequent experiments indicated that introducing that NSD2 glitch into cell lines in the lab ramped up activity of the enzyme encoded by NSD2 and produced an H3K36 dimethylation signature resembling that detected in the original screen. Moreover, the mutation appeared to bolster cancer-related cell features such as invasiveness and proliferation.

The NSD2 mutations were not only limited to ALL cell lines, but also turned up in samples obtained directly from children with cancer. When researchers scoured sequences from targeted NSD2 sequencing experiments on 1,021 pediatric cancer samples, they found NSD2 mutations in 19 of the tumors.

All but one of the NSD2 mutation-containing tumors were from individuals with ALL — particularly those with forms of the disease stemming from B-progenitor cells, the team reported. And 15 of the 19 NSD2 alterations involved the same point mutation described in the original ALL tumor set.

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