MicroRNA Expression and Response to Sorafenib, Cytarabine, and Idarubicin in Patients with Acute Myeloid Leukemia
MP Powers, JR Rushton, H Yao, BA Barkoh, D Jones, R Luthra. BCM, Houston, TX; MDACC, Houston, TX
Background: MicroRNA gene expression has been correlated with mutation status and prognosis in acute myeloid leukemia (AML). AML often has gain of function mutations in the tyrosine kinase FLT3 via either an internal tandem duplication (ITD) or kinase domain point mutation (KD). Sorafenib is a multi-kinase inhibitor which has been shown to target the FLT3 kinase in vitro and has shown promise in treating both FLT3 positive and negative leukemia when combined with the induction agents idarubicin and cytarabine. The molecular correlates of FLT3 response are not yet known. We evaluated the utility of miRNA profiling in identifying responsive AML.
Design: 17 patients treated with IAS (6 responders and 11 non-responders) had total RNA extracted from their diagnostic leukemia sample. 565 miRs were profiled with microarrays (Exiqon) with additional miRs profiled by TaqMan RT-PCR(Applied Biosystems). SAM analysis and the t-test were done on the 129 highest and most variable expressed genes to identify the genes differentially expressed between responders and non-responders and those that correlate with mutations in FLT3 (50% mutated), NPM1 (41% mutated), and CEBPA (29% mutated) mutations and myeloid v. monocytic blast phenotype.
Results: Unsupervised hierarchical clustering revealed miRNA expression patterns segregated primarily based on FLT3 mutation status and were similar to those previously reported (i.e. miR-10 family) but were not associated with IAS response. miR-660 was the most significantly upregulated in the non-responders (P<0.003), whereas members of the miRNA-181 family were upregulated in the responders The miR-181 family also correlated with the myeloid blast phenotype and were higher in the CEBPA mutated cases. miR-660 showed a week association with CEBPA mutation status and cellular phenotype.
Conclusions: A higher level of miR-660 expression correlates with the lack of response to IAS in AML patients. Conversely, the miR-181 family was expressed at a higher level in responders and correlated with CEBPA mutation status, a known good prognostic marker, and with the myeloid blast phenotype. Comparisons of markers of response of IAS to IA-alone will allow assessment of the specificity and utility of these miRNA biomarkers in personalized AML therapy.
Category: Pan-genomic/Pan-proteomic Approaches to Diseases
Monday, March 22, 2010 1:00 PM
Poster Session II # 227, Monday Afternoon