Mittal Pooja, Battaglin Francesca, Baca Yasmine, Xiu Joanne, Farrell Alex, Soni Shivani, Lo Jae Ho, Torres-Gonzalez Lesly, Algaze Sandra, Jayachandran Priya, Ashouri Karam, Wong Alexandra, Zhang Wu, Yu Jian, Zhang Lin, Weinberg Benjamin A, Lou Emil, Shields Anthony F, Goldberg Richard M, Marshall John L, Goel Sanjay, Singh Indrakant K, Lenz Heinz-Josef
Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Department of Zoology, Deshbandhu College, University of Delhi, New Delhi, India.
Int J Cancer. 2025 Apr 15;156(8):1583-1593. doi: 10.1002/ijc.35304. Epub 2024 Dec 30.
Myeloid cell leukemia 1 (MCL-1) is a member of the B-cell lymphoma 2 protein family and has anti-apoptotic functions. Deregulation of MCL-1 has been reported in several cancers, including lung and breast cancer. In the present study, the association of MCL-1 expression with molecular features in colorectal cancer (CRC) has been highlighted. CRC samples from Caris Life Sciences (Phoenix, AZ) were analyzed using NextGen DNA sequencing, whole transcriptome sequencing, whole exome sequencing, and immunohistochemistry (IHC); and stratified based on MCL-1 expression as top quartile MCL-1 (Q4) and bottom quartile MCL-1 (Q1). Immune cell infiltration (CI) in the tumor microenvironment (TME) was measured using RNA deconvolution analysis (QuanTIseq). MCL-1 tumors were associated with an increased rate of programmed death ligand 1 IHC, higher T cell-inflamed signature, interferon score, microsatellite instability-high and tumor mutational burden-high status. MCL-1 was associated with higher mutation rates of BCOR, TP53, KMT2D, ASXL1, KDM6A, ATM, MSH6, SPEN, KRAS, STK11, GNAS, RNF43, and lower mutation rates of CDKN1B, NRAS, and APC, and copy number amplifications in several genes. MCL-1 TME had higher CI of M1 and M2 macrophages, B cells, natural killer cells, neutrophils, and T-regulatory cells infiltration, and lower CI of myeloid dendritic cells. Higher MCL-1 expression is significantly associated with favorable clinical outcomes in CRC cohorts. Our data showed a strong correlation between MCL-1 and distinct immune biomarkers and TME CI in CRC. Our findings suggest MCL-1 is a potential modulator of antitumor immunity, TME, and biomarker in CRC.
髓系细胞白血病1（MCL-1）是B细胞淋巴瘤2蛋白家族的成员，具有抗凋亡功能。据报道，在包括肺癌和乳腺癌在内的多种癌症中，MCL-1存在失调现象。在本研究中，重点探讨了MCL-1表达与结直肠癌（CRC）分子特征之间的关联。使用二代DNA测序、全转录组测序、全外显子组测序和免疫组织化学（IHC）对来自凯瑞斯生命科学公司（亚利桑那州凤凰城）的CRC样本进行分析；并根据MCL-1表达分为上四分位数MCL-1（Q4）和下四分位数MCL-1（Q1）进行分层。使用RNA反卷积分析（QuanTIseq）测量肿瘤微环境（TME）中的免疫细胞浸润（CI）。MCL-1高表达的肿瘤与程序性死亡配体1 IHC阳性率增加、更高的T细胞炎症特征、干扰素评分、微卫星高度不稳定和肿瘤突变负荷高状态相关。MCL-1与BCOR、TP53、KMT2D、ASXL1、KDM6A、ATM、MSH6、SPEN、KRAS、STK11、GNAS、RNF43的较高突变率相关，与CDKN1B、NRAS和APC的较低突变率以及多个基因的拷贝数扩增相关。MCL-1高表达的TME中M1和M2巨噬细胞、B细胞、自然杀伤细胞、中性粒细胞和调节性T细胞浸润的CI较高，而髓样树突状细胞的CI较低。在CRC队列中，较高的MCL-1表达与良好的临床结局显著相关。我们的数据显示MCL-1与CRC中不同的免疫生物标志物和TME CI之间存在强相关性。我们的研究结果表明，MCL-1是CRC中抗肿瘤免疫、TME和生物标志物的潜在调节因子。
