Concurrent inhibition of MYC and BCL2 is a potentially effective treatment strategy for double hit and triple hit B-cell lymphomas.
Double hit lymphoma or triple hit lymphoma (DHL/THL) is a rare form of aggressive B-Cell Lymphoma. Overexpression of MYC, BCL2 or/and BCL6 due to genomic rearrangements are the key molecular features of DHL/THL. Patients with DHL/THL show very aggressive disease course and poor survival due to the lack of effective treatment modalities. Here, we established new THL cell model and assessed its in vitro growth characteristics along with the DHL cell line in response to potent MYC inhibitors, 10058-F4 and JQ-1, and a BCL2 inhibitor, ABT-199, with or without chemotherapeutic agent vincristine or doxorubicin. We found that 10058-F4, JQ-1 or ABT-199 exposure as a single agent inhibited the growth of DHL/THL cells in a dose-dependent manner. Combined exposure of 10058-F4 or JQ-1 and ABT-199 as well as vincristine or doxorubicin markedly suppressed the growth of DHL/THL cells compared with the single treatment. As assessed by multiple approaches, apoptosis induced by ABT-199, 10058-F4 or JQ-1 was underlying cause of the observed growth suppression. These findings suggest that co-inhibition of MYC and BCL2 signaling is a promising therapeutic strategy for patients with DHL/THL lymphomas.
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Munevver
M
Cinar
Tower Hematology Oncology Medical Group, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Fred
F
Rosenfelt
Tower Hematology Oncology Medical Group, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Sepehr
S
Rokhsar
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Jean
J
Lopategui
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Raju
R
Pillai
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Melissa
M
Cervania
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Andy
A
Pao
Department of Medicine and Hematology/Oncology and Division of Cancer Biology, Cedars-Sinai Medical Center, Los Angeles, CA, United States; Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States. Electronic address: bekir.cinar@cshs.org.
Bekir
B
Cinar
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States. Electronic address: serhan.alkan@cshs.org.
Serhan
S
Alkan
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use; D016259:Genes, myc; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000627:therapeutic use
D019086:Bridged Bicyclo Compounds, Heterocyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C579720:venetoclax
ABT-199; Aggressive B-cell lymphomas; BCL2; Double-hit and triple-hit lymphomas; JQ-1; MYC