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
  • Comments (1)
  • Email
  • ShareThis
  • Print
  • Download
  • Text Size A A A

Eleventh Hour

When a person with advanced leukemia has blood drawn, the fluid that comes out is thin, watery, and pinkish. This is because the spongy tissue inside the person’s bone marrow, which is where all blood cells are manufactured, is now devoting itself almost exclusively to producing monstrously deformed cancerous white blood cells.

By the time Myrrah Shapoo arrived at CUMC in January 2015, her blood had a ghostly translucence. She was also beginning to feel lethargic, the first sign of oxygen deprivation. Without treatment, she likely would die within days or weeks — either from infection or from her oxygen-starved organs shutting down.

To stabilize her, a team of physicians led by Maria Luisa Sulis ’15PH, a childhood-leukemia specialist, opted to give her a cocktail of chemotherapy drugs similar to the one she had received during her first few months of treatment in India. Based on the course that Myrrah’s disease had taken, they could tell that those drugs had done a decent job of combating her cancer.

“The problem seemed to have occurred later, with the drug she was given at the end of her treatment, after her cancer levels had dropped so low as to be undetectable,” says Sulis. “Our goal now was to knock her cancer cells back down to that level and keep her alive long enough for the genetic analysts to help us figure out a more personalized path to take.”

Soon after Sajid and Myrrah arrived at Columbia, the rest of the family joined them in the United States. They stayed with cousins in New Jersey and would make the long commute to the intensive-care unit of CUMC’s pediatric cancer ward every day. When Myrrah was strong, the family would Skype with relatives back home. When Myrrah felt too ill to socialize, Sajid or Rubina would read her stories from a collection of Indian adventure tales or simply cuddle with her on her tiny bed.

“Back in New Jersey each night, I’d bury myself in scientific papers about the genetics of leukemia,” says Sajid, a handsome and gentle-natured man of forty-one. “It was important to me that I try to understand what was going on with my daughter’s disease. Somehow that made the situation more tolerable.”

"We were told that Myrrah's disease might be treatable, but that it would require an unusually in-depth investigation to figure out how. This was our only chance." — Rubina Shapoo

As Myrrah fought for her life, clinicians and scientists from several CUMC departments and research laboratories joined forces to figure out a treatment plan. First on the case were pathologists at CUMC’s Laboratory of Personalized Genomic Medicine, a diagnostic facility that provides genetic testing for a wide range of diseases. They had received a vial of Myrrah’s blood and bone-marrow tissue the day after she arrived at the hospital and had immediately gone to work extracting DNA from both her cancerous white blood cells and her healthy cells. After processing the DNA, they loaded it onto a glass slide, which they placed into a computerized sequencing machine. The sequencer, which painstakingly examined strands of DNA to determine the identity of all thirty million nucleotides in the protein-coding genes of each cell, then downloaded two composite genetic blueprints: one representing a typical cancer cell in Myrrah’s bloodstream, and the other its healthy counterpart. Next, software designed by bioinformaticians in the laboratory organized that data into spreadsheets that highlighted the differences between the two. This would enable scientists to spot not only mutations in Myrrah’s cancer cells but also differences between the DNA in Myrrah’s noncancerous cells and the DNA of an average human cell — as represented by the findings of the Human Genome Project.

“What comes next is a massive cross-referencing project, in which you’re searching for commonalities among the genetic mutations you find in the patient and those that have been documented as possibly contributing to leukemia,” says Mahesh Mansukhani, an associate professor of clinical pathology who, as director of the Laboratory of Personalized Genomic Medicine, oversees the genetic sequencing and analysis done as part of PIPseq. “Your analysis goes in both directions — you see if the patient carries any mutations described in the scientific literature, and you scan the literature for references to variations that the child is carrying.”

Mansukhani and other members of his lab began analyzing Myrrah’s genetic profile three days after she was admitted. Over the next several weeks, they would consult regularly with pathologists, data specialists, and oncologists from other CUMC labs to help them determine which statistical correlations were most relevant. This is crucial, Mansukhani says, because a team of analysts could easily spend years searching for meaningful patterns in data sets as vast as those his team wrestles with.

“Consider that you’re looking at nineteen thousand plus genes in this child, and that fifteen or twenty genetic aberrations have so far been definitely linked to acute lymphoblastic leukemia,” says Mansukhani. “That doesn’t sound like an impossible puzzle to solve, right? But consider that each of those genes linked to leukemia has numerous mutated forms, each of which may have a different physiological effect. And consider that dozens of other genetic errors have been hypothesized to contribute to leukemia in small numbers of kids who have rare subtypes of the disease. Now it’s becoming a very complex mathematical problem, right? Meanwhile, you’ve got a child whose family is depending on you to solve this puzzle pretty darn quickly. So you’d better have a plan about what you’re looking for when you turn on your computer.”

One Girl’s Illness, Decoded

By early February 2015, a picture began to emerge of what was making Myrrah’s disease so stubborn. The first breakthrough occurred when Susan Hsiao, a molecular pathologist in Mansukhani’s group, discovered that Myrrah’s cancer cells carried a mutation in a gene called NT5C2. This mutated gene does not cause cancer, but it can derail a patient’s treatment by making leukemia cells resistant to certain chemotherapy drugs, including 6-mercaptopurine, or 6-MP. One of the first chemotherapy drugs ever invented, 6-MP is often given to leukemia patients in the very last stage of treatment in what is called the “maintenance” period of chemotherapy. Myrrah had received it every day for nearly two years, from the spring of 2013 through the end of 2014.

  • Email
  • ShareThis
  • Print
  • Recommend (27)
Log in with your UNI to post a comment

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!

The best stories wherever you go on the Columbia Magazine App

Maybe next time