Comprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-positive AML Defines Novel Therapeutic Options - A COG and TARGET Pediatric AML Study.

TitleComprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-positive AML Defines Novel Therapeutic Options - A COG and TARGET Pediatric AML Study.
Publication TypeJournal Article
Year of Publication2019
AuthorsSmith JL, Ries RE, Hylkema T, Alonzo TA, Gerbing RB, Santaguida MT, Brodersen LEidenschin, Pardo L, Cummings CL, Loeb KR, Le Q, Imren S, Leonti AR, Gamis AS, Aplenc R, E Kolb A, Farrar JE, Triche TJ, Nguyen C, Meerzaman D, Loken MR, Oehler VG, Bolouri H, Meshinchi S
JournalClin Cancer Res
Date Published2019 Nov 12
ISSN1078-0432
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 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 presence of this fusion was highly associated with adverse outcome (p<0.001) across all morphological 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 up-regulation of genes with cell membrane/extracellular matrix localization potential, including NCAM1 and GABRE. Additionally, miRNA profiling revealed significant over-expression 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 ADC 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.

DOI10.1158/1078-0432.CCR-19-1800
Alternate JournalClin. Cancer Res.
PubMed ID31719049
Grant ListU10 CA180886 / CA / NCI NIH HHS / United States
U10 CA180899 / CA / NCI NIH HHS / United States