AML at older age: age-related gene expression profiles reveal a paradoxical down-regulation of p16INK4A mRNA with prognostic significance.
Acute myeloid leukemia (AML) has a different clinical and biologic behavior in patients at older age. To gain further insight into the molecular differences, we examined a cohort of 525 adults to compare gene expression profiles of the one-third of youngest cases (n = 175; median age 31 years) with the one-third of oldest cases (n = 175; median age 59 years). This analysis revealed that 477 probe sets were up-regulated and 492 probe sets were down-regulated with increasing age at the significance level of P < .00001. After validation with 2 independent AML cohorts, the 969 differentially regulated probe sets on aging could be pointed to 41 probe sets, including the tumor-suppressor gene CDKN2A (encoding p16(INK4A)). In contrast to the induced p16(INK4A) expression that is associated with physiologic aging, p16(INK4A) is down-regulated in AML samples of patients with increasing age. However, this was only noticed in the intermediate- and unfavorable-risk group and not in the favorable-risk group and the molecularly defined subset "NPM1 mutant without FLT3-ITD." Multivariate analysis revealed p16(INK4A), besides cytogenetic risk groups, as an independent prognostic parameter for overall survival in older patients. We conclude that, in addition to altered clinical and biologic characteristics, AML presenting at older age shows different gene expression profiles.
de Jonge
Hendrik J M
HJ
Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
de Bont
Eveline S J M
ES
Valk
Peter J M
PJ
Schuringa
Jan Jacob
JJ
Kies
Marcel
M
Woolthuis
Carolien M
CM
Delwel
Ruud
R
Veeger
Nic J G M
NJ
Vellenga
Edo
E
Löwenberg
Bob
B
Huls
Gerwin
G
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D055815:Young Adult
D019941:Cyclin-Dependent Kinase Inhibitor p16; C000716967:NPM1 protein, human; D012333:RNA, Messenger; D000090243:Nucleophosmin