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The t8;21 and Inv16 translocations disrupt the normal function of core binding factors alpha CBFA and beta CBFB, respectively. These translocations represent two of the most common genomic abnormalities in acute myeloid leukemia AML patients, occurring in approximately 25% pediatric and 15% of adult with this malignancy. Both translocations are associated with favorable clinical outcomes after intensive chemotherapy, and given the perceived mechanistic similarities, patients with these translocations are frequently referred to as having CBF-AML. It remains uncertain as to whether, collectively, these translocations are mechanistically the same or impact different pathways in subtle ways that have both biological and clinical significance. Therefore, we used transcriptome sequencing RNA-seq to investigate the similarities and differences in genes and pathways between these subtypes of pediatric AMLs. Diagnostic RNA from patients with t8;21 N = 17, Inv16 N = 14, and normal karyotype NK, N = 33 were subjected to RNA-seq. Analyses compared the transcriptomes across these three cytogenetic subtypes, using the NK cohort as the control. A total of 1291 genes in t8;21 and 474 genes in Inv16 were differentially expressed relative to the NK controls, with 198 genes differentially expressed in both subtypes. The majority of these genes 175-198; binomial test p-value < 10−30 are consistent in expression changes among the two subtypes suggesting the expression profiles are more similar between the CBF cohorts than in the NK cohort. Our analysis also revealed alternative splicing events ASEs differentially expressed across subtypes, with 337 t8;21-specific and 407 Inv16-specific ASEs detected, the majority of which were acetylated proteins p = 1.5x10-51 and p = 1.8x10-54 for the two subsets. In addition to known fusions, we identified and verified 16 de novo fusions in 43 patients, including three fusions involving NUP98 in six patients. Clustering of differentially expressed genes indicated that the homeobox HOX gene family, including two transcription factors MEIS1 and NKX2-3 were down-regulated in CBF compared to NK samples. This finding supports existing data that the dysregulation of HOX genes play a central role in biology CBF-AML hematopoiesis. These data provide comprehensive transcriptome profiling of CBF-AML and delineate genes and pathways that are differentially expressed, providing insights into the shared biology as well as differences in the two CBF subsets.



Author: Chih-Hao Hsu, Cu Nguyen, Chunhua Yan, Rhonda E. Ries, Qing-Rong Chen, Ying Hu, Fabiana Ostronoff, Derek L. Stirewalt, George Koma

Source: http://plos.srce.hr/



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