Photo by Aaron Logan
Preclinical research has revealed potential therapeutic options for TCF3-HLF-positive acute lymphoblastic leukemia (ALL).
Investigators discovered a range of mutations in this subtype of ALL and identified features that appear to contribute to treatment resistance.
However, the team also found that TCF3-HLF-positive ALL is sensitive to treatment with glucocorticoids, anthracyclines, and certain agents in clinical development.
The BCL2-specific inhibitor venetoclax (ABT-199) proved particularly active against the disease.
Jean-Pierre Bourquin, MD, PhD, of the University Children’s Hospital Zurich in Switzerland, and his colleagues reported these findings in Nature Genetics.
The investigators sequenced samples from patients with TCF3-HLF-positive ALL and found a range of mutations. Most samples (67%) had deletions in PAX5, and most of the samples without PAX5 deletions had deletions in VPREB1.
The team also found recurrent mutations of TCF3, a new fusion gene (KHDRBS1-LCK), and activating mutations in RAS signaling pathway genes (NRAS, KRAS, and PTPN11), among other mutations.
After additional investigation, Dr Bourquin and his colleagues hypothesized that the initiating TCF3-HLF fusion in this disease occurs in a B-cell progenitor, and the specific lineage context is constrained further in a restricted developmental stage by additional mutations.
The investigators also tested various treatments in mouse models of TCF3-HLF-positive ALL. They observed resistance to dasatinib, nucleotide analogs, mitotic spindle inhibitors, and polo-like and aurora kinase inhibitors.
On the other hand, the disease was sensitive to glucocorticoids, mTOR inhibitors, anthracyclines, bortezomib, the HSP90 inhibitor AUY922, and panobinostat.
The team also found evidence suggesting that BCL2 might promote leukemic cell survival and constitute a druggable target in TCF3-HLF-positive ALL. So they tested the BCL2 inhibitor venetoclax in the mice.
A 2-week course of daily venetoclax significantly delayed leukemia progression, and xenografts from relapsed patients and those with minimal residual disease remained sensitive to venetoclax. The drug also exhibited synergistic effects when combined with vincristine or dexamethasone.
“Further studies are now needed to test how the results of our study might be used for therapeutic possibilities,” Dr Bourquin concluded.
