de Jonge Hendrik J M, de Bont Eveline S J M, Valk Peter J M, Schuringa Jan Jacob, Kies Marcel, Woolthuis Carolien M, Delwel Ruud, Veeger Nic J G M, Vellenga Edo, Löwenberg Bob, Huls Gerwin
Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Blood. 2009 Oct 1;114(14):2869-77. doi: 10.1182/blood-2009-03-212688. Epub 2009 Aug 10.
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.
急性髓系白血病（AML）在老年患者中具有不同的临床和生物学行为。为了进一步深入了解分子差异，我们研究了一组525名成年人，以比较最年轻的三分之一病例（n = 175；中位年龄31岁）与最年长的三分之一病例（n = 175；中位年龄59岁）的基因表达谱。该分析显示，在P <.00001的显著性水平下，随着年龄增长，477个探针集上调，492个探针集下调。在用2个独立的AML队列进行验证后，969个与衰老相关的差异调节探针集可指向41个探针集，包括肿瘤抑制基因CDKN2A（编码p16(INK4A)）。与生理衰老相关的诱导性p16(INK4A)表达相反，在年龄增长的AML患者样本中p16(INK4A)下调。然而，这仅在中危和高危组中观察到，在低危组以及分子定义的子集“NPM1突变而无FLT3-ITD”中未观察到。多变量分析显示，除细胞遗传学风险组外, p16(INK4A)是老年患者总生存的独立预后参数。我们得出结论，除了临床和生物学特征改变外，老年AML还表现出不同的基因表达谱。
