Potential Targeted Therapy Found for Newly Identified Leukemia Subtype with Poor Outcome

An international research team led by St. Jude Children's Research Hospital investigators has uncovered details of a new, high-risk subtype of acute lymphoblastic leukemia (ALL) as well as a possible targeted therapy. The findings were published online on November 8, 2016 in the open-access journal Nature Communications. The article is titled “Genomic Analyses Identify Recurrent MEF2D Fusions In Acute Lymphoblastic Leukemia.” The subtype is characterized by chromosomal rearrangements that involve the MEF2D gene and one of six partner genes, most often the gene BCL9. This subtype is called MEF2D-rearranged ALL. "MEF2D is a transcription factor that switches on expression of other genes during normal development," said corresponding author Charles Mullighan, M.D., M.B.B.S., a member of the St. Jude Department of Pathology. "We found that MEF2D chromosomal rearrangements disrupt expression of those genes and create a vulnerability to at least one targeted therapy, the drug panobinostat." Genomic analysis of more than 1,700 children, adolescents, and adults with ALL identified 42 with MEF2D rearrangements. Researchers calculated that MEF2D-rearranged ALL accounts for 5.3 percent of the almost 30 percent of ALL cases whose genetic basis was unknown. The MEF2D-rearranged subtype occurred most frequently in adolescents and was associated with reduced survival compared to some other ALL subtypes. Panobinostat inhibits the activity of a family of proteins including HDAC9. Researchers showed that MEF2D-rearranged leukemic cells produced high levels of HDAC9. Investigators tested panobinostat in the laboratory and found the drug stopped proliferation of human MEF2D-rearranged leukemic cells.
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