Abstract
<div>Abstract<p><b>Purpose:</b> This study was conducted to identify novel genes with importance to the biology of adult acute myelogenous leukemia (AML).</p><p><b>Experimental Design:</b> We analyzed DNA from highly purified AML blasts and paired buccal cells from 95 patients for recurrent genomic microdeletions using ultra-high density Affymetrix single nucleotide polymorphism 6.0 array–based genomic profiling.</p><p><b>Results:</b> Through fine mapping of microdeletions on 17q, we derived a minimal deleted region of ∼0.9-Mb length that harbors 11 known genes; this region includes <i>Neurofibromin 1</i> (<i>NF1</i>). Sequence analysis of all <i>NF1</i> coding exons in the 11 AML cases with <i>NF1</i> copy number changes identified acquired truncating frameshift mutations in two patients. These <i>NF1</i> mutations were already present in the hematopoetic stem cell compartment. Subsequent expression analysis of NF1 mRNA in the entire AML cohort using fluorescence-activated cell sorting sorted blasts as a source of RNA identified six patients (one with a <i>NF1</i> mutation) with absent NF1 expression. The NF1 null states were associated with increased Ras-bound GTP, and short hairpin RNA–mediated NF1 suppression in primary AML blasts with wild-type NF1 facilitated colony formation in methylcellulose. Primary AML blasts without functional NF1, unlike blasts with functional NF1, displayed sensitivity to rapamycin-induced apoptosis, thus identifying a dependence on mammalian target of rapamycin (mTOR) signaling for survival. Finally, colony formation in methylcellulose <i>ex vivo</i> of NF1 null CD34+/CD38− cells sorted from AML bone marrow samples was inhibited by low-dose rapamycin.</p><p><b>Conclusions:</b> NF1 null states are present in 7 of 95 (7%) of adult AML and delineate a disease subset that could be preferentially targeted by Ras or mammalian target of rapamycin–directed therapeutics. Clin Cancer Res; 16(16); 4135–47. ©2010 AACR.</p></div>
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