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

Abstract

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.

A Bayesian model for unsupervised detection of RNA splicing based subtypes in cancers

“…Next, given the possible functional consequences of splicing changes between the identified tiles in many AML associated genes, we hypothesized that our splicing based patient grouping could improve clinical decisions that are based on mutation analysis alone. Notably, the added value of splicing changes to AML classification has been shown recently for FLT3 -ITD and NPM1 for FAB classification AML genes 38 as well as RUNX1 and SF3B1 39 . To assess usefulness of combining splicing changes and mutations to predict drug response, we prioritize FLT3 -ITD and Sorafenib and NPM1 and Venetoclax due to reliable mutation calls and their prominent role in AML clinical diagnosis.…”

High Mitochondrial Protein Expression as a Potential Predictor of Relapse Risk in Acute Myeloid Leukemia Patients with the Monocytic FAB Subtypes M4 and M5

“…Recently, Wojtuszkiewicz et al found that there is maturation state-specific differential splicing of genes associated with cell cycle control and DNA damage in FLT3 -ITD and NPM1 -mutated AML blasts. Intriguingly, the number of genes that displayed differential splicing was significantly higher in the FAB M4 subtype, with a total of 1438 splicing events, compared with the FAB M1 and M2 subtypes, each with about 200 splicing events [ 63 ].…”

A New Molecular (P)Layer in Pseudomyxoma Peritonei: The Splicing Machinery is Dysregulated and Linked to Low Survival

“…Actually, the enrichment analysis also reveals links to other interleukins as 4, 13 and 20 families, further suggesting a relationship with immunoregulatory processes and in ammation that would mark the tumor microenvironment. Finally, FTL3 tyrosine kinase receptor mechanisms have been linked to a variety of tumors, including hepatocellular carcinoma [40] and acute myeloid leukemia [41]. In the latter, it is worth noting that the numerous splicing-related alterations have enabled to establish different tumors groups, based on the pathways to which differentially spliced genes belong.…”