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Preventing Transportation of Mutant Protein Can Inhibit Growth of Leukemic Cells


Researchers at Baylor College of Medicine have found that preventing a mutated protein from leaving the nucleus and traveling to the cytoplasm of the cell can help inhibit the growth of leukemic cells in acute myeloid leukemia.

Mutant NPM1 genes that abnormally transport out of the nucleus and into the cytoplasm of the cell have been found to drive the growth of leukemic cells, according to a new study published in Cancer Cell.

The mutated NPM1 creates abnormal cytoplasmic localization of the mutant protein (NPM1c), which can be targeted in treatment. NPM1 is a commonly mutated gene in acute myeloid leukemia (AML) and can be found in 20% to 30% of cases; if NPM1c remains in the nucleus, it can be used to differentiate AML cells.

Researchers at Baylor College of Medicine utilized CRISPR technology to target and manipulate the mutant form of the protein.

“While it has long been recognized that mutated NPM1 plays an important role in AML, no one has determined how the normal versus mutated forms of the protein NPM1 function. It is one of the biggest enigmas in acute myeloid leukemia,” Margaret Goodell, PhD, professor in the Center for Stem Cells and Regenerative Medicine and in the Departments of Pediatrics and Molecular and Human Genetics at Baylor, and senior author of the paper, said in a statement.

A new screening tool can predict risk of AML years before it develops.

Preventing NPM1c from leaving the nucleus and moving into the cytoplasm—using either CRISPR or a cancer drug—can inhibit leukemic cell growth. The researchers found in culture dishes that blocking the transportation of the mutant protein caused leukemic cells to disappear. Furthermore, mice with leukemia who were treated in this manner lived longer.

According to the researchers, the study shows that AML cells resulting in mutant NPM1 are highly dependent on NPM1c exporting from the nucleus to proliferate and the use of nuclear export inhibitor therapeutics should be used.

“This research has profound therapeutic implications,” said Lorenzo Brunetti, MD, postdoctoral associate in the Goodell Lab at Baylor and co-first author of the paper. “There is already a drug available that inhibits the export of multiple proteins, including mutant NPM1, from the nucleus to the cytoplasm. This gives us reasonable evidence that we can treat this type of AML with an existing therapy. We hope this research opens the door for larger conversations and continued research to spur a clinical trial.”


Brunetti L, Gundry MC, Sorcini D, et al. Mutant NPM1 maintains the leukemic state through HOX expression. Cancer Cell. 2018;34(3):499-512.E9.

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