Data from Comprehensive Transcriptome Profiling of Cryptic CBFA2T3–GLIS2 Fusion–Positive AML Defines Novel Therapeutic Options: A COG and TARGET Pediatric AML Study
Year: 2023
Type: other
Abstract: Purpose: A cryptic inv(16)(p13.3q24.3) encoding the CBFA2T3–GLIS2 fusion is associated with poor outcome in infants with acute megakaryocytic leukemia. We aimed to broaden our understanding of the pathogenesis of this fusion through transcriptome profiling. Experimental Design: Available RNA from children and young adults with de novo acute myeloid leukemia (AML; N = 1,049) underwent transcriptome sequencing (mRNA and miRNA). Transcriptome profiles for those with the CBFA2T3–GLIS2 fusion (N = 24) and without (N = 1,025) were contrasted to define fusion-specific miRNAs, genes, and pathways. Clinical annotations defined distinct fusion-associated disease characteristics and outcomes. Results: The CBFA2T3–GLIS2 fusion was restricted to infants <3 years old (P < 0.001), and the presence of this fusion was highly associated with adverse outcome (P < 0.001) across all morphologic classifications. Further, there was a striking paucity of recurrent cooperating mutations, and transduction of cord blood stem cells with this fusion was sufficient for malignant transformation. CBFA2T3–GLIS2 positive cases displayed marked upregulation of genes with cell membrane/extracellular matrix localization potential, including NCAM1 and GABRE. Additionally, miRNA profiling revealed significant overexpression of mature miR-224 and miR-452, which are intronic miRNAs transcribed from the GABRE locus. Gene-set enrichment identified dysregulated Hippo, TGFβ, and hedgehog signaling, as well as NCAM1 (CD56) interaction pathways. Therapeutic targeting of fusion-positive leukemic cells with CD56-directed antibody–drug conjugate caused significant cytotoxicity in leukemic blasts. Conclusions: The CBFA2T3–GLIS2 fusion defines a highly refractory entity limited to infants that appears to be sufficient for malignant transformation. Transcriptome profiling elucidated several highly targetable genes and pathways, including the identification of CD56, providing a highly plausible target for therapeutic intervention.
Authors: Jenny L. Smith, Rhonda E. Ries, Tiffany Hylkema, Todd A. Alonzo, Robert B. Gerbing, Marianne T. Santaguida, Lisa Eidenschink Brodersen, Laura Pardo, Carrie L. Cummings, Keith R. Loeb, Quy Le, Suzan Imren, Amanda R. Leonti, Alan S. Gamis, Richard Aplenc, E. Anders Kolb, Jason E. Farrar, Timothy J. Triche, Cu Nguyen, Daoud Meerzaman, Michael R. Loken, Vivian G. Oehler, Hamid Bolouri, Soheil Meshinchi
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4361957708