Our previous studies revealed an increase in alternative splicing (AS) of multiple RNAs in leukemic cells from patients with acute myeloid leukemia (AML) compared to CD34+ bone marrow cells from normal donors (NDs). Aberrantly spliced genes included a number of oncogenes, tumor suppressor genes, and genes involved in regulation of apoptosis, cell cycle, and cell differentiation. Among the most commonly mis-spliced genes (> 70% of AML patients) were two, NOTCH2 and FLT3, genes that encode myeloid cell surface proteins. The splice-variants of NOTCH2 and FLT3 resulted from complete or partial exon skipping and utilization of cryptic splice sites. Longitudinal analyses suggested that aberrant splicing of NOTCH2 and FLT3 correlated with disease status. Correlation analyses between splice-variants of these genes and clinical features of patients showed an association between NOTCH2 splice-variants and overall survival of patients. Our results suggest that NOTCH2 and FLT3 mis-splicing is a common characteristic of AML and has the potential to generate transcripts encoding proteins with altered function. Thus, splice-variants of these genes might provide disease markers and targets for novel therapeutics.