Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance

Abstract

T lymphocyte non-Hodgkin's lymphoma (T-NHL) represents an aggressive and largely therapy-resistant subtype of lymphoid malignancies. As deregulated apoptosis is a frequent hallmark of lymphomagenesis, we analyzed gene expression profiles and protein levels of primary human T-NHL samples for various apoptotic regulators. We identified the apoptotic regulator MCL-1 as the only pro-survival BCL-2 family member to be highly expressed throughout all human T-NHL subtypes. Functional validation of pro-survival protein members of the BCL-2 family in two independent T-NHL mouse models identified that the partial loss of Mcl-1 significantly delayed T-NHL development in vivo. Moreover, the inducible reduction of MCL-1 protein levels in lymphoma-burdened mice severely impaired the continued survival of T-NHL cells, increased their susceptibility to chemotherapeutics and delayed lymphoma progression. Lymphoma viability remained unaffected by the genetic deletion or pharmacological inhibition of all alternative BCL-2 family members. Consistent with a therapeutic window for MCL-1 treatment within the context of the whole organism, we observed an only minimal toxicity after systemic heterozygous loss of Mcl-1 in vivo. We conclude that re-activation of mitochondrial apoptosis by blockade of MCL-1 represents a promising therapeutic strategy to treat T-cell lymphoma.

MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically

“…In line with previous reports in alternative cancer cohorts 12 , 22 , genomic gains of MCL-1 occurred at higher frequency than any other BCL-2 family member and did not cause compensatory deregulation of other BCL-2 protein family members, as detected in the TCGA and TRACERx datasets. This has already been shown in hepatocellular carcinoma 28 , B cell-non-Hodgkin’s lymphoma 29 and T cell lymphoma 23 , 30 , 31 . However, dependencies on other pro-survival BCL-2 family members may exist depending on the type of cancer and treatment used, as recently reported data on breast cancer showed a positive correlation between not only MCL-1 but also BCL-2A1 expression and an inverse association with BCL-2 expression 26 .…”

BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines

“…Analysis of large cancer genome datasets revealed that the genomic region containing MCL1 is amplified in $10% of cancers (Beroukhim et al, 2010). Of note, inducible gene deletion in pre-clinical murine models of cancer showed that MCL-1 is essential for the sustained expansion of acute myeloid leukemia (AML) (Glaser et al, 2012), c-MYC-or BCR-ABL-driven pre-B or B cell lymphomas (Kelly et al, 2014;Koss et al, 2013), T cell lymphomas driven by loss of p53 or other oncogenic lesions Spinner et al, 2016), and multiple myeloma (MM) Morales et al, 2011). The development of S63845 provided the first opportunity to test an MCL-1-selective BH3-mimetic drug in pre-clinical cancer models (Kotschy et al, 2016).…”

Survival control of malignant lymphocytes by anti-apoptotic MCL-1

“…Within pro-survival BCL-2 members, myeloid cell leukemia-1 (MCL-1) was identified as an important anti-apoptotic protein in several lymphoma subtypes. [1][2][3] Interestingly, despite BCL-2 and MCL-1 being the only anti-apoptotic BCL-2 family members that are located on chromosomal fragile sites (Table 1), MCL-1 is rarely a target for chromosomal translocation. A possible reason for this difference may lie in a recombination hotspot intersecting with the BCL-2, but not the MCL-1, gene.…”