Mihashi Yasuhito, Mizoguchi Mikio, Takamatsu Yasushi, Ishitsuka Kenji, Iwasaki Hiromi, Koga Monji, Urabe Kazunori, Momosaki Seiya, Sakata Toshifumi, Kiyomi Fumiaki, Takeshita Morishige
Departments of *Pathology †Otolaryngology ‡Internal Medicine, Division of Medical Oncology, Hematology and Infectious Disease ¶Dermatology, Faculty of Medicine ††Academia, Industry and Government Collaborative Research Institute of Translational Medicine for Life Innovation, Fukuoka University Departments of ∥Hematology #Dermatology **Pathology, Clinical Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka §Division of Hematology and Immunology, Kagoshima University, Kagoshima, Japan.
Am J Surg Pathol. 2017 Aug;41(8):1139-1149. doi: 10.1097/PAS.0000000000000871.
Smoldering-type and chronic-type adult T-cell leukemia/lymphomas (ATLL) patients have relatively indolent clinical courses, but often progress into aggressive lymphoma-type and acute-type disease. We examined the roles of transcription factor C-MYC and its ubiquitin ligase FBXW7 in tumor tissues from 137 patients with ATLL. Immunohistochemical tests showed ≥50% of lymphoma cells in 78.7% (48/61) of lymphoma-type, and 64.9% (24/37) of acute-type samples expressed C-MYC, significantly higher than was seen in smoldering-type (3.6%) and chronic-type (9.1%) samples (P<0.01). Real-time polymerase chain reaction showed C-MYC mRNA expression in lymphoma-type and acute-type samples were significantly higher than in smoldering-type (P<0.01). C-MYC expression was highly correlated with its mRNA levels (ρ=0.65, P<0.0001), chromosomal amplification and duplication (ρ=0.3, P=0.045) and MIB1 labeling index (ρ=0.69, P<0.0001). Expression of FBXW7 protein and mRNA in lymphoma-type samples were significantly lower than those of smoldering-type (P<0.01 for each), and both were inversely correlated with C-MYC (protein: ρ=-0.4, P=0.0002; mRNA: ρ=-0.31, P=0.015). Seven patients with smoldering-type or chronic-type ATLL converted to acute-type, in 4 of whom C-MYC expression increased from <50% to ≥50%. Patients with ≥50% C-MYC or MIB1 had significantly worse prognosis than those with <50% C-MYC (P=0.0004) or MIB1 (P<0.0001), as did those with ≥7.5 C-MYC mRNA scores (P=0.033); whereas significantly better prognosis was associated with ≥50% FBXW7 protein (P=0.0006) or ≥0.17 FBXW7 mRNA (P=0.016). C-MYC and FBXW7 affect ATLL proliferation and progression, and low FBXW7 may increase C-MYC expression. C-MYC was a critical prognostic factor in ATLL patients.
冒烟型和慢性型成人T细胞白血病/淋巴瘤（ATLL）患者的临床病程相对惰性，但常进展为侵袭性淋巴瘤型和急性型疾病。我们检测了137例ATLL患者肿瘤组织中转录因子C-MYC及其泛素连接酶FBXW7的作用。免疫组织化学检测显示，淋巴瘤型样本中78.7%（48/61）、急性型样本中64.9%（24/37）的淋巴瘤细胞中≥50%表达C-MYC，显著高于冒烟型（3.6%）和慢性型（9.1%）样本（P<0.01）。实时聚合酶链反应显示，淋巴瘤型和急性型样本中C-MYC mRNA表达显著高于冒烟型（P<0.01）。C-MYC表达与其mRNA水平（ρ=0.65，P<0.0001）、染色体扩增和重复（ρ=0.3，P=0.045）以及MIB1标记指数（ρ=0.69，P<0.0001）高度相关。淋巴瘤型样本中FBXW7蛋白和mRNA表达显著低于冒烟型（各P<0.01），且两者均与C-MYC呈负相关（蛋白：ρ=-0.4，P=0.0002；mRNA：ρ=-0.31，P=0.015）。7例冒烟型或慢性型ATLL患者转变为急性型，其中4例C-MYC表达从<50%增加至≥50%。C-MYC或MIB1≥50%的患者预后显著差于C-MYC<50%（P=0.0004）或MIB1<50%（P<0.0001）的患者，C-MYC mRNA评分≥7.5的患者也是如此（P=0.033）；而FBXW7蛋白≥50%（P=0.0006）或FBXW7 mRNA≥0.17（P=0.016）与显著更好的预后相关。C-MYC和FBXW7影响ATLL的增殖和进展，低FBXW7可能增加C-MYC表达。C-MYC是ATLL患者的关键预后因素。
