COVER STORY

Meet the Girl with Gene NUP214-ABL1

When Myrrah Shapoo arrived at Columbia University Medical Center last year with a form of cancer that wouldn’t respond to chemotherapy, a team of physicians and scientists working on a new precision-medicine initiative faced their ultimate test.

by David J. Craig Published Summer 2016
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“She had variants in others genes linked to cancer, too, but this one stuck out as being the most immediately relevant to her care,” says Hsiao. “It provided a perfect explanation for why she had relapsed.”

The mutation that Hsiao found in Myrrah’s NT5C2 gene was the simplest type of genetic aberration there is: a point mutation, which is the result of a single nucleotide being missing, inserted where it doesn’t belong, or swapped out for another. In Myrrah’s version of NT5C2, the 1,219th of its 1,683 nucleotides, which should have been a guanine molecule, was a thymine molecule.

Leukemia Researchers Alberto Ambesi-Impiombato and Adolfo Ferrando

Hsiao says that in the course of her analysis she will sometimes contact scientists who have studied a particular gene to discuss the clinical ramifications of the variation she has found. In this case, her job was easier than usual: the scientist who had first described NT5C2’s role in chemotherapy resistance was a CUMC leukemia researcher named Adolfo Ferrando. Ferrando is an expert on the genetic and molecular basis of the disease, and in 2013, his research team had analyzed the genes of 140 leukemia patients who had relapsed after receiving 6-MP or a closely related drug. The scientists had found that 15 percent of the patients had mutated versions of NT5C2.

“Adolfo’s team was able to confirm that a point mutation at that location was likely to cause problems,” says Hsiao.

Now Myrrah’s physicians knew what drug not to give her. But what should they give her instead? To answer this question, the PIPseq team turned again to Ferrando, whose laboratory is among several at CUMC that regularly provide analytic support to the pediatric oncologists. Ferrando’s team, in addition to analyzing the chemical composition of DNA, can analyze the RNA and proteins made by genes and determine which genes are active and which are inactive, both in normal development and in cancer.

“Genes are not static entities,” says Ferrando. “They turn on and off, often as a result of their interactions with other genes. And sometimes you need that level of understanding to tease out what’s happening in a particular person’s disease.”

In April, Alberto Ambesi-Impiombato, a postdoctoral researcher in Ferrando’s group, made an important discovery. Using a computational technique called cluster analysis, he observed that hundreds of genes in Myrrah’s cancer cells were turning on and off in a pattern that suggested her disease shared deep similarities with the form of ALL that is caused when a part of chromosome 9 fuses onto chromosome 22, resulting in what is known as the Philadelphia chromosome. The drug Gleevec was designed specifically to treat that form of ALL; it works by dismantling a mutant protein produced by the Philadelphia chromosome that tells other molecules inside of a cell to continually make the cell divide.

“So now the question was whether or not this patient’s disease was driven by a similar mechanism,” says Ferrando. “And if it was, perhaps Gleevec or a similar drug might be used therapeutically.”

In 2014, the pediatric oncology unit at CUMC became one of the first in the world to offer whole-exome sequencing to every child with cancer in its care.

Maria Luisa Sulis, the physician overseeing Myrrah’s care and herself a former laboratory scientist, solved the final piece of the puzzle. She ordered targeted DNA tests to look for a handful of genetic mutations that are known to cause malfunctions in a cell’s metabolic signaling very similar to those caused by the Philadelphia chromosome. And they found one: in Myrrah’s cancer cells, one entire gene in chromosome 9 had been folded back onto its neighbor so that their nucleotides mixed to create a hybrid gene known as NUP214-ABL1. The protein manufactured by this hybrid gene had previously been shown to act similarly to the one produced by the Philadelphia chromosome, instructing a cell to incessantly divide.

“This was a chromosomal rearrangement much smaller and more difficult to spot than the Philadelphia chromosome,” says Mansukhani. “You wouldn’t see this one unless you analyzed how the DNA expresses itself as RNA.”

The finding was all the more remarkable because it pointed to a specific treatment strategy. In 2006, the pharmaceutical company Bristol-Myers Squibb released a drug called Sprycel, which works very similarly to Gleevec, targeting the specific types of proteins that both the Philadelphia chromosome and the NUP214-ABL1 gene produce. Experiments had shown that Sprycel would be particularly effective in Myrrah’s case.

So now the path forward was clear: Myrrah’s doctors would add Sprycel to the traditional chemotherapy cocktail she was receiving, and continue giving her the drug for as long as it took to wipe out any remaining cancer cells.

Hope for Others

On a recent Wednesday morning, about twenty-five Columbia physicians and medical researchers gathered in a conference room at CUMC to update one another on cases they were working on as part of the PIPseq program. Mansukhani took the floor first, presenting his team’s analyses of the DNA of several children recently admitted to the hospital. He spoke in the dense, super specialized language of genetics, using alphanumeric code to describe the glitches in the children’s genes. “We found a mutation at c.884C>T, p.P295 in 104 of one thousand cells,” he said, referring to a young boy with a tumor. The physicians peppered him with questions: “Isn’t that in the same region as the famous Sonic Hedgehog mutation?” “Would we expect to find a mutation there in someone with this kind of tumor?” “What does this tell us about his chances of relapse?” Andrew Kung, after presiding over a lengthy discussion of the case, summarized the group’s consensus: the physicians should start the boy on a standard chemotherapy regimen, and the analysts would continue looking for clues about what experimental drugs he might be given, should he need an alternative.

After the meeting, Kung expressed his excitement at seeing physicians and medical researchers collaborating so intimately: “Five years ago, that wouldn’t have happened. It’s our ability to bring together experts from across the entire medical center that makes precision medicine work.”

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Comments

Outstanding article. Grateful that there are so many individuals dedicated towards finding the various cures for cancer. This research is different and exciting. Talk about thinking out of the box! Thank you!

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