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June 16, 2014

SickKids scientists uncover possible genetic cause for leukemia spread to brain

Researchers at The Hospital for Sick Children (SickKids) have uncovered a genetic defect in acute lymphoblastic leukemia (ALL) cells that promotes their invasion of the brain, part of the central nervous system (CNS).  The findings, recently published in Genes & Development, could lead to the development of therapies that specifically prevent ALL spread to the CNS, which is a serious complication. Currently, curing children with ALL often requires injections of chemotherapy directly into the CNS to limit leukemia growth; however these therapies can also cause long-term health issues.

“If we can find therapies to prevent leukemia spread to the brain, instead of injecting chemotherapy into the brain, that would be huge,” says Dr. Cynthia Guidos, senior author of the study and Senior Scientist in Developmental & Stem Cell Biology at SickKids. “Our findings suggest that drugs targeting the functions controlled by a gene called Flt3 could help block leukemic cell growth in the CNS, and may be less toxic than current treatments.”

Using a mouse model, researchers found that CNS-invading leukemias expressed high levels of a gene called Flt3, in contrast to leukemias that did not spread to the CNS.  Flt3 normally regulates the growth of immature white blood cells and then turns off. This study showed that these leukemias expressed a defective version of Flt3 that cannot be turned off, suggesting that Flt3 allows the leukemic cells to invade the CNS.

The researchers then transferred the defective Flt3 gene into mouse leukemia cells that don’t usually invade the brain; this abnormal Flt3 gene endowed them with the ability to spread to the CNS confirming the importance of this gene.

The team also demonstrated that a Flt3-targeted drug, now in clinical trials for treating other cancers, stopped growth of the CNS leukemia cells in cell culture dishes.

Dr. Guidos says that next steps for this research will be to investigate whether Flt3 also plays an important role in promoting CNS invasion of human ALL. Her team will use frozen cells from the SickKids leukemia cell bank, which contains frozen samples from over 100 patients, to do just that.

This research was funded by the Ontario Institute for Cancer Research Cancer Stem Cell Program and Genome Canada through the Ontario Genomics Institute.