Age-specific differences in oncogenic pathway dysregulation and anthracycline sensitivity in patients with acute myeloid leukemia.
OBJECTIVE
To define the biology driving the aggressive nature of acute myeloid leukemia (AML) in elderly patients.


METHODS
Clinically annotated microarray data from 425 patients with newly diagnosed de novo AML from two publicly available data sets were analyzed after age-specific cohorts (young <or= 45 years, n = 175; elderly >or= 55 years; n = 144) were prospectively identified. Gene expression analysis was conducted utilizing gene set enrichment analysis, and by applying previously defined and tested signature profiles reflecting dysregulation of oncogenic signaling pathways, altered tumor environment, and signatures of chemotherapy sensitivity.


RESULTS
Elderly AML patients as expected had worse overall survival and event-free survival compared with younger patients. Analysis of oncogenic pathways revealed that older patients had higher probability of RAS, Src, and tumor necrosis factor (TNF) pathway activation (all P < .0001). Older patients were also less sensitive to anthracycline compared with younger patients with AML (P < .0001). Hierarchical clustering revealed that younger AML patients in cluster 2 had clinically worse survival, with high RAS, Src, and TNF pathway activation and in turn were less sensitive to anthracycline compared with patients in cluster 1. However, among elderly patients with AML, those in cluster 1 also demonstrated high RAS, Src, and TNF pathway activation but this did not translate into differences in survival or anthracycline sensitivity.


CONCLUSIONS
AML in the elderly represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathway variations that contributes to poor survival and anthracycline resistance. These insights should enable development and adjustments of clinically meaningful treatment strategies in the older patient population.
Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC 27708, USA. rao00012@mc.duke.edu
Arati V
AV
Rao
Peter J M
PJ
Valk
Klaus H
KH
Metzeler
Chaitanya R
CR
Acharya
Sascha A
SA
Tuchman
Marvaretta M
MM
Stevenson
David A
DA
Rizzieri
Ruud
R
Delwel
Christian
C
Buske
Stefan K
SK
Bohlander
Anil
A
Potti
Bob
B
Löwenberg
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000008:administration & dosage* / Q000009:adverse effects; D015331:Cohort Studies; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011336:Probability; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018943:Anthracyclines; D051941:fms-Like Tyrosine Kinase 3