Inhibition of MCL1 induces apoptosis in anaplastic large cell lymphoma and in primary effusion lymphoma

Abstract

Overexpression of antiapoptotic BCL2 family proteins occurs in various hematologic malignancies and contributes to tumorigenesis by inhibiting the apoptotic machinery of the cells. Antagonizing BH3 mimetics provide an option for medication, with venetoclax as the first drug applied for chronic lymphocytic leukemia and for acute myeloid leukemia. To find additional hematologic entities with ectopic expression of BCL2 family members, we performed expression screening of cell lines applying the LL-100 panel. Anaplastic large cell lymphoma (ALCL) and primary effusion lymphoma (PEL), 2/22 entities covered by this panel, stood out by high expression of MCL1 and low expression of BCL2. The MCL1 inhibitor AZD-5991 induced apoptosis in cell lines from both malignancies, suggesting that this BH3 mimetic might be efficient as drug for these diseases. The ALCL cell lines also expressed BCLXL and BCL2A1, both contributing to survival of the cells. The combination of specific BH3 mimetics yielded synergistic effects, pointing to a novel strategy for the treatment of ALCL. The PI3K/mTOR inhibitor BEZ-235 could also efficiently be applied in combination with AZD-5991, offering an alternative to avoid thrombocytopenia which is associated with the use of BCLXL inhibitors.

Expression Ratios of the Anti-Apoptotic BCL2 Family Members Dictate the Selective Addiction of KSHV-Transformed Primary Effusion Lymphoma Cell Lines to MCL1

“…In contrast, both cell lines are resistant to BCL2i and BCL-xLi. These results are consistent with a study showing that PEL cell lines are sensitive to another MCL1i inhibitor AZD-5991 but are resistant to the dual BCL2/BCL-xL inhibitor ABT-263 (31).…”

“…In contrast, BCL2 expression is detectable only in BC-1 and BC-3, while we do not detect A1 or Diva in any of the cell lines. Similar expression patterns of MCL1, BCL2, and BCL-xL were recently reported in additional PEL cell lines (29). Together, our data indicate that PEL cell lines express the other BCL2 family proteins, but are selectively addicted to MCL1.…”

“…In contrast, BCL2 expression is detectable only in BC-1 and BC-3 cells, while we do not detect A1 or Diva in any of the cell lines. Similar expression patterns of MCL1, BCL2, and BCL-xL were recently reported in additional PEL cell lines (31).…”

A novel risk model based on anoikis: Predicting prognosis and immune infiltration in cutaneous melanoma

“…Myeloid cell leukemia-1 ( MCL1 ), a typical anti-apoptotic protein belonging to the oncogenic BCL-2 family, was originally identified in myeloid cells ( Reissig et al, 2022 ). MCL1 has been found to be overexpressed in many solid tumors, and many studies highlighted the potential importance of MCL1 as a therapeutic target ( Pereira-Castro et al, 2022 ; Quentmeier et al, 2022 ). It is worth noting that demethylzeylasteral was found to evoke the apoptosis of melanoma cells by downregulating the level of MCL1 ( Zhao et al, 2017 ).…”

Last but not least: BFL-1 as an emerging target for anti-cancer therapies

“…Recently, unbiased genome wide CRISPR activation screens revealed a dominant role for A1 in venetoclax resistance in a novel model of aggressive lymphoma [ 57 ]. Furthermore, high BFL-1 levels were reported in ALCL cell lines which are resistant to MCL-1 or BCL-XL inhibitors, and siRNA knockdown of BCL2A1 induced apoptosis in drug resistant cells [ 58 ]. Finally, a study of 27 T cell lymphoma patients showed that previously chemotherapy-treated patients exhibited significantly higher levels of BCL2A1 expression compared to untreated patients [ 59 ].…”