Maturation State-Specific Alternative Splicing in FLT3-ITD and NPM1 Mutated AML

Cancers

Jeroen J. W. M. Janssen¹  Gert J. Ossenkoppele¹  Inge van der Werf¹  Jacqueline Cloos¹  Anna Wojtuszkiewicz¹  Wencke Walter²  Constance Baer²  Stephan Hutter²  Claudia Haferlach²  Wolfgang Kern²  Torsten Haferlach² 

[1]Department of Hematology, Amsterdam University Medical Center, VU University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands

[2]MLL Munich Leukemia Laboratory, 81377 Munich, Germany

关键词: alternative splicing;    acute myeloid leukemia;    FLT3-ITD;    NPM1;    FAB;    maturation state;   

DOI  :  10.3390/cancers13163929

来源: DOAJ

【 摘 要 】

Despite substantial progress achieved in unraveling the genetics of AML in the past decade, its treatment outcome has not substantially improved. Therefore, it is important to better understand how genetic mutations translate to phenotypic features of AML cells to further improve response predictions and to find innovative therapeutic approaches. In this respect, aberrant splicing is a crucial contributor to the pathogenesis of hematological malignancies. Thus far, altered splicing is well characterized in relation to splicing factor mutations in AML. However, splicing profiles associated with mutations in other genes remain largely unexplored. In this study, we explored differential splicing profiles associated with two of the most common aberrations in AML: FLT3-ITD and NPM1 mutations. Using RNA-sequencing data of a total of 382 primary AML samples, we found that the co-occurrence of FLT3-ITD and mutated NPM1 is associated with differential splicing of FAB-type specific gene sets. Despite the FAB-type specificity of particular gene sets, the primary functions perturbed by differential splicing in all three FAB types include cell cycle control and DNA damage response. Interestingly, we observed functional divergence between alternatively spliced and differentially expressed genes in FLT3-ITD+/NPM1+ samples in all analyzed FAB types, with differential expression affecting genes involved in hematopoietic differentiation. Altogether, these observations indicate that concomitant FLT3-ITD and mutated NPM1 are associated with the maturation state-specific differential splicing of genes with potential oncogenic relevance.

【 授权许可】

Unknown