| Title | Comprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-positive AML Defines Novel Therapeutic Options - A COG and TARGET Pediatric AML Study. |
| Publication Type | Journal Article |
| Year of Publication | 2019 |
| Authors | Smith 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 |
| Journal | Clin Cancer Res |
| Date Published | 2019 Nov 12 |
| ISSN | 1078-0432 |
| 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. |
| DOI | 10.1158/1078-0432.CCR-19-1800 |
| Alternate Journal | Clin. Cancer Res. |
| PubMed ID | 31719049 |
| Grant List | U10 CA180886 / CA / NCI NIH HHS / United States U10 CA180899 / CA / NCI NIH HHS / United States |