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of Bcl-2 family proteins to address clinical response to cytarabine-based therapy in
patients with AML (Pierceall et al. 2013 ). Peripheral blood mononuclear cell or
bone marrow aspirate specimens were obtained from newly diagnosed patients with
AML, viably preserved, and assayed by fl ow cytometry following BH3 profi le assay
with individual BH3 peptides. When patients were stratifi ed by cytogenetic status,
readout was signifi cant for both intermediate and unfavorable risk groups, demon-
strating predictive power independent of cytogenetics. Additional analyses of sec-
ondary clinical endpoints displayed correlation between overall survival and
event-free survival when patients were stratifi ed by peptide response. Taken
together, these results highlight the potential utility of BH3 profi ling in personalized
diagnostics of AML by offering actionable information for patient management
decisions. Eutropics Pharmaceuticals’ PraediCare technology to develop a compan-
ion diagnostic for leukemia is based on BH3 profi ling.
Several mutations that contribute to the pathogenesis of AML remain undefi ned
and the relationships between patterns of mutations and epigenetic phenotypes
continue to be investigated to improve an understanding of pathomechanism of
AML as a basis for personalized management. Genomes of 200 clinically anno-
tated adult cases of de novo AML have been analyzed, using either WGS (50 cases)
or WES (150 cases), along with RNA and miRNA sequencing and DNA-
methylation analysis (The Cancer Genome Atlas Research Network 2013 ). Results
show that AML genomes have fewer mutations than most other adult cancers. At
least one potential driver mutation was identifi ed in nearly all AML samples. This
mutation was in one of nine categories of genes that are almost certainly relevant
for pathogenesis, including transcription-factor fusions the gene encoding nucleo-
phosmin, tumor- suppressor genes, DNA-methylation-related genes, signaling
genes, chromatin- modifying genes, myeloid transcription-factor genes, cohesin-
complex genes, and spliceosome-complex genes. A complex interplay of genetic
events was found to contribute to AML pathogenesis in individual patients.
Integrated of the expression data for both mRNA and miRNA with all the clinical
and mutational data for all genomes in this study revealed that the differentiation
state of the AML samples was highly correlated with the expression signature, as
reported previously. Patients who had PML-RARA fusions had very distinct
mRNA and miRNA signatures that were strongly correlated with each other and
with a specifi c DNA methylation signature. All the transcription factor fusions
were correlated with specifi c patterns of mRNA expression, whereas PML-RARA
and RUNX1-RUNX1T1 (and some MLL fusions) were also associated with
miRNA expression signatures. In addition, occurrence of NPM1, DNMT3A, and
FLT3 mutations together was strongly associated with specifi c expression signa-
tures for both mRNA and miRNA. These data suggest that this combination of
mutations in patients with intermediate-risk AML may identify a subtype of AML
with unique epigenetic features. The databases from this study are widely available
to serve as a foundation for further investigations of AML pathogenesis, classifi ca-
tion, and risk stratifi cation.
10 Personalized Therapy of Cancer