HIF1α Expression Is Associated with NPM1 Mutation, but Not IDH1 or IDH2 Mutations in Acute Myeloid Leukemia with Normal Karyotype
Shimin Hu, Vivian Ruvolo, Hongbo Lu, Hagop M Kantarjian, David Wheeler, Donna M Muzny, L Jeffrey Medeiros, Carlos Bueso-Ramos, Marina Konopleva, Michael Andreeff, Sergej Konoplev. University of Texas MD Anderson Cancer Center, Houston; Baylor College of Medicine, Houston
Background: Hypoxia-inducible factor (HIF)-1α is a key regulator of cellular response to hypoxia. We reported that acute lymphoblastic leukemia (ALL) progression is associated with expansion of bone marrow (BM) hypoxic areas, and that hypoxia contributes to ALL chemoresistance (Benito et al. PLoS One, 2011). HIF-1α activity also can be induced in tumor cells via many oncogenic stimuli. Expression of HIF-1α, whose stability is negatively regulated by α-ketoglutarate-involved prolyl-hydroxylation, is upregulated in gliomas harboring isocitrate dehydrogenase 1 (IDH1) mutations. IDH1 and IDH2 gene mutations also have been implicated in the pathogenesis of AML with diploid cytogenetics. Here we investigate HIF-1α expression in adult cases of AML.
Design: HIF-1α expression was assessed by immunohistochemistry (H1alpha67, Novus Biologicals, Littleton, CO) in BM biopsy specimens. All coding exons of IDH1 and IDH2 were sequenced as described (Clin Cancer Res 16: 1597, 2010). Mutations of exon 12 of NPM1 were determined by PCR followed by direct sequencing. Mutations of FLT3 and codons 12 and 61 of N-RAS and K-RAS were assessed by PCR.
Results: We studied 156 AML pts with normal karyotype, 89 men and 67 women, with a median age of 66 years (range, 18-90). 90 pts achieved complete remission (CR), and three-year survival was 24% (CI, 20-27%). HIF-1α was expressed in BM of 90 (58%) AML cases, but not in 15 normal BM. IDH1 mutations were detected in 10 (6%), IDH2 mutations in 22 (14%) pts, and NPM1 mutations in 24/111 (22%) pts. HIF-1α expression was associated with mutated NPM1 (19/24 (79%) vs. 44/87 (51%), p=0.02). There was a trend toward more frequent HIF-1α expression in AML with IDH mutations (22/32, 69%) vs. AML with wild type IDH (68 /124, 55%), p=0.16. HIF-1α expression was not associated with the FLT3-ITD, FLT3-D835, or RAS mutations. Pts with IDH mutations had a significantly lower CR rate compared to IDH wild type (34% vs. 64%, p<0.005). There was no statistical difference in overall survival among HIF-1α positive vs. HIF-1α negative AML pts.
Conclusions: HIF-1α is expressed in the majority of AML pts while sparingly expressed in normal BM. HIF is stabilized among all molecular subtypes of AML, suggesting that marrow hypoxia rather than specific genetic abnormalities is a main molecular mechanism driving HIF expression in AML and that HIF-1α is a potential therapeutic target in AML pts. Further studies are ongoing to delineate the possible contribution of mutated NPM1 to HIF-1α stability.
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 205, Tuesday Morning