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Whitehead Institute, National Genetic Database

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Whitehead Institute ‘Screen’ Detects Mutations Linked to Drug Resistance

Researchers at the Whitehead Institute for Biomedical Research said they have devised a way to identify gene mutations responsible for resistance to certain targeted cancer drugs before they are prescribed.

Scientists said the screen can identify mutations that cause patients with chronic myeloid leukemia to become resistant to Gleevec. The drug targets the protein produced by BCR/ABL, the gene that causes this rare form of leukemia.

“In the leukemia cells of a CML patient, BCR/ABL is constantly mutating,” said George Daley, leader of the research team that developed the screening strategy. “Cells carrying certain mutations can resist the drug and continue to grow while the remainder of leukemia cells are suppressed. We have found a way to discover those mutations experimentally.”

Gleevec binds to a specific pocket within the BCR/ABL kinase domain, and all mutations previously found in CML patients who relapsed while taking Gleevec have been found in that domain. But the researchers discovered that many of the mutations exist in other parts of the protein — some at “great distances from the drug-binding pocket and thought to have no direct involvement with drug binding,” they said.

Writing in the March 21 Cell, the scientists used recombinant DNA methodologies to randomly mutate the BCR/ABL gene to mimic potential variations that might occur in CML patients. They then transferred the mutated genes into murine blood cells and exposed them to Gleevec. While most cells succumbed to the drug, some of the cells with specific variations thrived.

“We looked for those cells that continued to grow, extracted them and sequenced their genes,” Mohammad Azam, a postdoctoral researcher at Whitehead and lead author of this new study, said in a statement last week. That examination revealed 112 mutations researchers elsewhere had previously linked to Gleevec resistance in CML patients — 97 more than scientists currently knew of.

“Doctors could monitor patients’ leukemia at the molecular level for signs of impending resistance and decide when ... to switch medications,” said Daley.

The screening technique could also be used by pharmaceutical scientists involved in drug development, the researcher suggested: Scientists can detect the location of the variations that cause drug resistance to first-generation compounds, and “design drugs that remain effective despite the mutations.”

— KL


Despite Delays in Iceland’s National Genetic Database, DeCode Pushes On

Three years after Iceland’s Ministry of Health gave DeCode Genetics an exclusive license to create the Icelandic Health Sector Database, the database remains empty, according to a report last week in an online computer journal.

Difficulties in obtaining government approval together with financial troubles at the Icelandic pharmacogenomics company are putting into the question the project’s viability, said Computerworld.com. “The impression of everyone here is that the database will not be a reality,” the journal quoted historian Steindor Erlingsson as saying. Erlingsson is the author of Our Genes, a new book about DeCode that was published in Iceland.

Thanks to a 1998 law that ushered in the country’s health-record database, DeCode is not required to obtain consent from individual patients to use private medical data. However, the database itself must meet stringent security standards written by the government’s Data Protection Commission.

This is likely easier said than done. According to Hordur Helgi Helgason, deputy commissioner of the Data Protection Commission, the problem of segregating an individual’s identity from his or her medical information is “most challenging and most urgent to curb,” the journal reported. It added that Helgason said the commission had received and evaluated “about half of the material it will want to examine” to determine whether DeCode’s database “adequately protects” Icelanders’ private records.

Confounding this is the fact that DeCode has been “slower than either the government or the company expected” in delivering specifics on the database. At DeCode, these delays haven’t slowed its core gene-hunting efforts. To date, the company has collected disease data and DNA samples from 80,000 Icelanders, or roughly one-third of the nation’s population, the company said.

DeCode said it is still committed to the national database even though it admits it isn’t a linchpin of it the company’s overall success. “Our main work is finding genes linked to disease, and drug targets,” company spokesman Edward Farmer told the journal. “The Icelandic Health Sector Database is supposed to supplement the data we now have. …

“Our basic core of work is going very well and is not affected by this, but it’s something that we want to do,” he said.

— KL

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