Abstract
The TCF3–HLF fusion reprograms lymphoid-committed cells to a hybrid hematopoietic, drug-resistant state.
Major finding: The TCF3–HLF fusion reprograms lymphoid-committed cells to a hybrid hematopoietic, drug-resistant state.
Approach: The genomic landscape of TCF3–HLF-positive ALL was compared to that of TCF3–PBX1-positive ALL.
Impact: The BCL2 inhibitor venetoclax is a potential therapy for this incurable cancer.
Pediatric acute lymphoblastic leukemia (ALL) is characterized into molecular subtypes by the presence of recurrent aneuploidies or gene fusions, the latter of which encodes master hematopoietic regulators, such as fusion of the transcription factor TCF3 with pre-B-cell leukemia homeobox 1 (PBX1). Unlike TCF3–PBX1-positive ALL, tumors driven by the fusion of TCF3 with hepatic leukemia factor (HLF) represent a rare ALL subtype associated with relapse and poor prognosis. Fischer and colleagues compared the genomic and transcriptomic landscapes of primary TCF3–HLF-positive ALL with that of TCF3–PBX1-positive ALL using integrative sequencing analyses. TCF3 translocation breakpoints displayed features suggestive of a committed lymphoid progenitor cell of origin in TCF3–HLF-positive ALL. In contrast to TCF3–PBX1-positive ALL, TCF3–HLF-positive ALL exhibited mutations in the second TCF3 allele and was enriched for monoallelic PAX5 deletion; samples without PAX5 deletion frequently had VPREB1 or BTG1 deletions, suggesting that TCF3–HLF cooperates with disruption of genes that regulate the transition from progenitor to precursor B cells. Recurrent mutations in RAS pathway genes were detected in TCF3–HLF-positive ALL cells and likely conferred a selective proliferative advantage. Of note, gene set enrichment analysis revealed that TCF3–HLF-positive ALL cells had greater expression of hematopoietic stem cell and myeloid signatures and features of mesenchyme-derived tissues, suggesting that this fusion induces an immature hematopoietic, drug-resistant state via transcriptional reprogramming. Drug activity screening revealed that TCF3–HLF-positive ALL cells were resistant to standard ALL therapeutics but sensitive to other drugs, including glucocorticoids, mTOR inhibitors, and anthracyclines. In addition, TCF3–HLF-positive ALL samples exhibited increased expression of the proapoptotic protein BCL2 and were extremely sensitive to the BCL2 inhibitor venetoclax in patient-derived xenograft models; primary TCF3–HLF-positive ALL samples that were refractory to conventional chemotherapy also remained sensitive to venetoclax. These results provide insight into the unique genomic landscape of TCF3-HLF-positive ALL and identify several potential therapeutic targets.