Photo courtesy of Novartis
Researchers say they have identified a high-risk subtype of acute lymphoblastic leukemia (ALL) that may respond to treatment with the histone deacetylase (HDAC) inhibitor panobinostat.
The ALL subtype is characterized by chromosomal rearrangements that involve the MEF2D gene and 1 of 6 partner genes, most often BCL9.
The researchers described this subtype, known as MEF2D-rearranged ALL, in Nature Communications.
“MEF2D is a transcription factor that switches on expression of other genes during normal development,” said study author Charles Mullighan, MD, MBBS, of the St. Jude Children’s Research Hospital in Memphis, Tennessee.
“We found that MEF2D chromosomal rearrangements disrupt expression of those genes and create a vulnerability to at least one targeted therapy, the drug panobinostat.”
Dr Mullighan and his colleagues performed genomic analyses on samples from a total of 1724 children, adolescents, and adults with ALL. This revealed 52 patients with MEF2D rearrangements.
MEF2D-rearranged ALL
The researchers calculated that MEF2D-rearranged ALL accounted for 5.3% of the ALL cases whose genetic basis was unknown.
The team also noted that MEF2D-rearranged ALL occurred most frequently in adolescents. Although, overall, ALL occurs most often in children between 3 and 5 years old, the average patient with MEF2D-rearranged ALL was 14.
In addition, MEF2D-rearranged ALL was associated with reduced survival when compared to some other ALL subtypes. The 5-year cancer-free survival for MEF2D-rearranged ALL patients was 71.6%.
The researchers also found that a fusion protein resulting from the MEF2D rearrangement led to sustained growth of mouse cells when compared to wild-type MEF2D or other proteins.
“That indicates the MEF2D fusion is a key step in transforming a normal white blood cell with a finite lifespan into a leukemic cell that is immortal,” Dr Mullighan said.
Role for panobinostat
MEF2D-rearranged leukemic cells produced high levels of HDAC9, which is targeted by panobinostat.
The researchers tested panobinostat in the lab and found the drug stopped proliferation of human MEF2D-rearranged leukemic cells.
Dr Mullighan said MEF2D-rearranged leukemic cells were exquisitely sensitive to panobinostat, which suggested the drug might function in a more targeted manner against cells with the rearrangement.
“If further testing of panobinostat, either alone or in combination therapy, confirms the anti-proliferative activity, that would lay the foundation for a clinical trial in patients, particularly patients with high-risk disease or those who have relapsed,” he said.
