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Purpose: This study was conducted to identify novel genes with importance to the biology of adult acute myelogenous leukemia (AML).Experimental Design: 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.Results: 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 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 two 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 fluorescence-activated cell sorting sorted blasts as a source of RNA identified six patients (one with a NF1 mutation) with absent NF1 expression. The NF1 null states were associated with increased Rasbound 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 ex vivo of NF1 null CD34+/CD38− cells sorted from AML bone marrow samples was inhibited by low-dose rapamycin.Conclusions: 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.Cytogenetics and mutations in selected genes are of dominant importance to the biology and clinical outcome of patients with acute myelogenous leukemia (AML; refs. 1-7). Further, genomic changes based on karyotyping of blood or marrow specimens from patients with AML directly affect AML treatment decisions.Although the anatomy of recurrent chromosomal translocations and the functional consequences of translocationassociated fusion proteins are well studied, relatively less is known about the genes that are mutated or deregulated as a consequence of subchromosomal copy number changes. Efforts at mapping subchromosomal genomic copy number changes using array-based comparative genomic hybridization (CGH) or single nucleotide polymorphism (SNP) arrays in AML have identified genomic losses and gains, and candidate genes have been proposed (8-11).

Purpose: Genomic complexity is present in approximately 15% to 30% of all chronic lymphocytic leukemia (CLL) and has emerged as a strong independent predictor of rapid disease progression and short remission duration in CLL. We conducted this study to advance our understanding of the causes of genomic complexity in CLL.Experimental Design: We have obtained quantitative measurements of radiation-induced apoptosis and radiation-induced ATM autophosphorylation in purified CLL cells from 158 and 140 patients, respectively, and have used multivariate analysis to identify independent contributions of various biological variables on genomic complexity in CLL.Results: Here, we identify a strong independent effect of radiation resistance on elevated genomic complexity in CLL and describe radiation resistance as a predictor for shortened CLL survival. Furthermore, using multivariate analysis, we identify del17p/p53 aberrations, del11q, del13q14 type II (invariably resulting in Rb loss), and CD38 expression as independent predictors of genomic complexity in CLL, with aberrant p53 as a predictor of ∼50% of genomic complexity in CLL. Focusing on del11q, we determined that normalized ATM activity was a modest predictor of genomic complexity but was not independent of del11q. Through single nucleotide polymorphism array-based fine mapping of del11q, we identified frequent monoallelic loss of Mre11 and H2AFX in addition to ATM, indicative of compound del11q-resident gene defects in the DNA double-strand break response.Conclusions: Our quantitative analysis links multiple molecular defects, including for the first time del11q and large 13q14 deletions (type II), to elevated genomic complexity in CLL, thereby suggesting mechanisms for the observed clinical aggressiveness of CLL in patients with unstable genomes. Clin Cancer Res; 16(3); 835-47. ©2010 AACR.Genomic aberrations substantially influence the biology and clinical outcome of patients with chronic lymphocytic leukemia (CLL; refs. 1-3). The presence of specific chromosomal deletions, in particular del17p and del11q, allows for the identification of a subset of patients with shortened overall survival. Furthermore, CLL patients with chromosomal translocations, complex aberrant karyotypes, or elevated genomic complexity, as measured through single nucleotide polymorphism (SNP) arrays, have recently been shown to have aggressive CLL that is characterized by rapid disease progression and short remission duration (4-9). An ad hoc summary analysis of these published reports suggests that CLL cases with these latter genomic complexity characteristics are substantially more common than CLL with del17p or p53 mutations and that the overlap between these two groups of CLL is partial, thus implying the existence of additional unidentified factors that cause genomic complexity in CLL.Subchromosomal deletions, which are the quantitatively dominant genomic aberration in CLL, must have involved DNA double-strand breaks as intermediates. Given that the cellular response to DNA doub...

VDD is highly effective for initial treatment of MM followed by SCT in appropriate patients, and it has a reasonable safety profile. Achievement of VGPR or better with this initial therapy predicted longer PFS, regardless of the consolidation therapy given.