NF1 inactivation in adult acute myelogenous leukemia.
NF1 inactivation in adult acute myelogenous leukemia.
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DOI：
10.1158/1078-0432.ccr-09-2639
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发表时间：
2010-08-15
期刊：
影响因子：
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通讯作者：
Malek SN
中科院分区：
文献类型：
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作者：
Parkin B;Ouillette P;Wang Y;Liu Y;Wright W;Roulston D;Purkayastha A;Dressel A;Karp J;Bockenstedt P;Al-Zoubi A;Talpaz M;Kujawski L;Liu Y;Shedden K;Shakhan S;Li C;Erba H;Malek SN
This study was conducted to identify novel genes with importance to the biology of adult acute myelogenous leukemia (AML). We analyzed DNA from highly purified AML blasts and paired buccal cells from 95 patients for recurrent genomic microdeletions using ultra-high density Affymetrix SNP 6.0 array-based genomic profiling. Through fine mapping of microdeletions on 17q, we derived a minimal deleted region of ~0.9Mb length that harbors 11 known genes; this region includes Neurofibromin 1 (NF1). Sequence analysis of all NF1 coding exons in the 11 AML cases with NF1 copy number changes identified acquired truncating frameshift mutations in 2 patients. These NF1 mutations were already present in the hematopoetic stem cell compartment. Subsequent expression analysis of NF1 mRNA in the entire AML cohort using FACS sorted blasts as a source of RNA identified 6 patients (one with a NF1 mutation) with absent NF1 expression. The NF1 null states were associated with increased Ras-bound GTP, and shRNA-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 mTOR signaling for survival. Finally, colony formation in methylcellulose ex vivo of NF1 null CD34+/CD38− cells sorted from AML bone marrow samples was inhibited by low dose rapamycin. NF1 null states are present in 7/95=7% of adult AML and delineate a disease subset that could be preferentially targeted by Ras or mTOR-directed therapeutics.
