Alternative splicing redefines landscape of commonly mutated genes in acute myeloid leukemia
Menée à l'aide de lignées cellulaires et de cellules blastiques issues de patients atteints d'une leucémie myéloïde aiguë, cette étude met en évidence le rôle de l'épissage alternatif dans la dérégulation des gènes et analyse le mécanisme par lequel leur fonction peut être modifiée
Acute myeloid leukemia (AML) is an aggressive hematologic cancer in which malignant myeloid precursor cells impair hematopoiesis and induce bone marrow failure. Most genes associated with AML are mutated in less than 10% of patients, suggesting that alternative mechanisms of gene disruption contribute to this disease. Here, we demonstrate that alternative splicing provides an additional layer of gene dysregulation and mechanism by which gene function is disrupted in AML. These results demonstrate that classical mutation analysis underestimates the burden of functional gene disruption in AML and highlight the importance of assessing the contribution of alternative splicing to gene dysregulation in human disease.Most genes associated with acute myeloid leukemia (AML) are mutated in less than 10% of patients, suggesting that alternative mechanisms of gene disruption contribute to this disease. Here, we find a set of splicing events that alter the expression of a subset of AML-associated genes independent of known somatic mutations. In particular, aberrant splicing triples the number of patients with reduced functional EZH2 compared with that predicted by somatic mutation alone. In addition, we unexpectedly find that the nonsense-mediated decay factor DHX34 exhibits widespread alternative splicing in sporadic AML, resulting in a premature stop codon that phenocopies the loss-of-function germline mutations observed in familial AML. Together, these results demonstrate that classical mutation analysis underestimates the burden of functional gene disruption in AML and highlight the importance of assessing the contribution of alternative splicing to gene dysregulation in human disease.Newly generated RNA-Seq data from the PENN cohort, HL60, and MV411 cells have been deposited in the Gene Expression Omnibus (GSE142514).
Proceedings of the National Academy of Sciences , résumé, 2020