PMID- 38546691
OWN - NLM
STAT- Publisher
LR  - 20240328
IS  - 1592-8721 (Electronic)
IS  - 0390-6078 (Linking)
DP  - 2024 Mar 28
TI  - MYC overexpression in natural killer cell lymphoma: prognostic and therapeutic 
      implications.
LID - 10.3324/haematol.2023.283811 [doi]
AB  - The current clinical management of Extranodal NK/T-cell lymphoma (ENKTL) 
      primarily depends on conventional chemotherapy and radiotherapy, underscoring the 
      need for innovative therapeutic strategies. This study explores the clinical 
      significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we 
      identified MYC protein overexpression in approximately 75% of cases within a 
      large cohort of 111 patients. MYC overexpression was strongly correlated with 
      lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating 
      MYC expression into the PINK-E prognostic model significantly enhanced its 
      predictive power. Subsequently, we implemented MYC knockdown (KD) in NK 
      malignancy cell lines with MYC overexpression, resulting in significant viability 
      reduction. RNA-sequencing (RNA-seq) used to determine MYC function revealed a 
      high overlap with canonical MYC-regulated genes and enrichment in metabolism and 
      cell cycle regulation. Integrative analysis of the RNA-seq data upon MYC KD with 
      gene expression profiles of primary ENKTL cases identified a subset of genes 
      closely associated with MYC overexpression. Among these, CDK4 emerged as a 
      potential therapeutic target, and its inhibition not only abrogated MYC function 
      but also decreased MYC expression in NK malignancy cells. Furthermore, the 
      clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect 
      in xenograft mouse models, especially when combined with gemcitabine. In summary, 
      our study firmly establishes MYC as an oncogene with prognostic significance in 
      ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for 
      treating ENKTL with MYC overexpression.
FAU - Bi, Chengfeng
AU  - Bi C
AD  - Division of Oncology and Hematology, Department of Internal Medicine, University 
      of Nebraska Medical Center, Omaha, NE. andy.bi@unmc.edu.
FAU - Huang, Yuhua
AU  - Huang Y
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangzhou, Guangdong, China; Department of Pathology, Sun 
      Yat-sen University Cancer Center, Guangzhou, Guangdong.
FAU - Ali, Roshia
AU  - Ali R
AD  - Division of Oncology and Hematology, Department of Internal Medicine, University 
      of Nebraska Medical Center, Omaha, NE.
FAU - Wang, Fang
AU  - Wang F
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangzhou, Guangdong, China; Department of Molecular 
      Diagnosis, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong.
FAU - Yang, Xia
AU  - Yang X
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Guangzhou, Guangdong, China; Department of Pathology, Sun 
      Yat-sen University Cancer Center, Guangzhou, Guangdong.
FAU - Bouska, Alyssa
AU  - Bouska A
AD  - Department of Pathology and Microbiology, University of Nebraska Medical Center, 
      Omaha, NE.
FAU - Xu, Lu
AU  - Xu L
AD  - Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 
      USA; Department of Hematology, The First Affiliated Hospital of Hainan Medical 
      University, Haikou, Hainan.
FAU - Hao, Xinbao
AU  - Hao X
AD  - State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua 
      University, Beijing.
FAU - Lunning, Matthew A
AU  - Lunning MA
AD  - Division of Oncology and Hematology, Department of Internal Medicine, University 
      of Nebraska Medical Center, Omaha, NE.
FAU - Chan, Wing C
AU  - Chan WC
AD  - Department of Pathology, City of Hope National Medical Center, Duarte, CA.
FAU - Iqbal, Javeed
AU  - Iqbal J
AD  - Department of Pathology and Microbiology, University of Nebraska Medical Center, 
      Omaha, NE.
FAU - Weisenburger, Dennis D
AU  - Weisenburger DD
AD  - Department of Pathology and Microbiology, University of Nebraska Medical Center, 
      Omaha, NE.
FAU - Vose, Julie M
AU  - Vose JM
AD  - Division of Oncology and Hematology, Department of Internal Medicine, University 
      of Nebraska Medical Center, Omaha, NE.
FAU - Fu, Kai
AU  - Fu K
AD  - Department of Pathology and Microbiology, University of Nebraska Medical Center, 
      Omaha, NE, USA; Department of Pathology, Roswell Park Comprehensive Cancer 
      Center, Buffalo, NY. Kai.Fu@roswellpark.org.
LA  - eng
PT  - Journal Article
DEP - 20240328
PL  - Italy
TA  - Haematologica
JT  - Haematologica
JID - 0417435
SB  - IM
EDAT- 2024/03/28 12:47
MHDA- 2024/03/28 12:47
CRDT- 2024/03/28 11:43
PHST- 2023/08/07 00:00 [received]
PHST- 2024/03/28 12:47 [medline]
PHST- 2024/03/28 12:47 [pubmed]
PHST- 2024/03/28 11:43 [entrez]
AID - 10.3324/haematol.2023.283811 [doi]
PST - aheadofprint
SO  - Haematologica. 2024 Mar 28. doi: 10.3324/haematol.2023.283811.