Dysregulation of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins of the intrinsic apoptotic pathway is fundamental to the pathophysiology of many hematologic malignancies. The BCL-2 family ...consists of regulatory proteins that either induce apoptosis (proapoptotic) or inhibit it (prosurvival). BCL-2, myeloid cell leukemia-1, and B-cell lymphoma–extra large are prosurvival proteins that are prime targets for anticancer therapy, and molecules targeting each are in various stages of preclinical and clinical development. The US Food and Drug Administration (FDA)-approved BCL-2 inhibitor venetoclax was first proven to be highly effective in chronic lymphocytic leukemia and some B-cell non-Hodgkin lymphoma subtypes. Subsequently, venetoclax was found to be active clinically against a diverse array of hematologic malignancies including multiple myeloma, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, and others. Here, we give a brief introduction to BCL-2 family biology and the mechanism of action of BCL-2 Homology 3 (BH3) mimetics, and provide an overview of the clinical data for therapeutically targeting prosurvival proteins in hematologic malignancies, with a focus on BCL-2 inhibition. To prioritize novel agent combinations and predict responders, we discuss the utility of functional assays such as BH3 profiling. Finally, we provide a perspective on how therapies targeting BCL-2 family proteins may be optimally implemented into future therapeutic regimens for hematologic malignancies.
Intrinsic apoptosis, reliant on BAX and BAK, has been postulated to be fundamental for morphogenesis, but its precise contribution to this process has not been fully explored in mammals. Our ...structural analysis of BOK suggests close resemblance to BAX and BAK structures. Notably, Bok−/−Bax−/−Bak−/− animals exhibited more severe defects and died earlier than Bax−/−Bak−/− mice, implying that BOK has overlapping roles with BAX and BAK during developmental cell death. By analyzing Bok−/−Bax−/−Bak−/− triple-knockout mice whose cells are incapable of undergoing intrinsic apoptosis, we identified tissues that formed well without this process. We provide evidence that necroptosis, pyroptosis, or autophagy does not substantially substitute for the loss of apoptosis. Albeit very rare, unexpected attainment of adult Bok−/−Bax−/−Bak−/− mice suggests that morphogenesis can proceed entirely without apoptosis mediated by these proteins and possibly without cell death in general.
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•BOK, BAX, and BAK have similar structures and overlapping roles during development•BOK/BAX/BAK triple-null mice have more severe defects than BAX/BAK double knockouts•Intrinsic apoptosis is critical for midline fusion and aortic arch formation•A small number of BOK/BAX/BAK triple-null mice develop entirely without apoptosis
Although apoptosis has been observed in many organs and tissues during embryonic development, it is not strictly required for the development of most organs.
Radiation therapy induces immunogenic cell death, which can theoretically stimulate T cell priming and induction of tumor-specific memory T cell responses, serving as an
vaccine. In practice, this ...abscopal effect is rarely observed. We use two mouse models of pancreatic cancer to show that a single dose of stereotactic body radiation therapy (SBRT) synergizes with intratumoral injection of agonistic anti-CD40, resulting in regression of non-treated contralateral tumors and formation of long-term immunologic memory. Long-term survival was not observed when mice received multiple fractions of SBRT, or when TGFβ blockade was combined with SBRT. SBRT and anti-CD40 was so effective at augmenting T cell priming, that memory CD8 T cell responses to both tumor and self-antigens were induced, resulting in vitiligo in long-term survivors.
Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, and its receptor Fas are critical for the shutdown of chronic immune responses and prevention of autoimmunity. Accordingly, ...mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice and humans. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding. Here we generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized non-apoptotic activities. Mice lacking sFasL (FasL(Deltas/Deltas)) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL (FasL(Deltam/Deltam)) could not kill cells through Fas activation. FasL(Deltam/Deltam) mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasL(gld/gld) mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, FasL(Deltam/Deltam) mice (on a C57BL/6 background) succumbed to systemic lupus erythematosus (SLE)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in FasL(gld/gld) mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through non-apoptotic activities.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Understanding the critical factors that govern recovery of the hematopoietic system from stress, such as during anticancer therapy and bone marrow transplantation, is of clinical significance. We ...investigated the importance of the prosurvival proteins myeloid cell leukemia-1 (MCL-1) and B-cell lymphoma–extra large (BCL-XL) in stem/progenitor cell survival and fitness during hematopoietic recovery from stress. Loss of a single Mcl-1 allele, which reduced MCL-1 protein levels, severely compromised hematopoietic recovery from myeloablative challenge and following bone marrow transplantation, whereas BCL-XL was dispensable in both contexts. We identified inhibition of proapoptotic p53 upregulated modulator of apoptosis (PUMA) as the key role of MCL-1 in both settings, with Mcl-1+/−;Puma−/− mice completely protected from the deleterious effects of loss of 1 Mcl-1 allele. These results reveal the molecular mechanisms that govern cell survival during hematopoietic recovery from stress.
•Small changes in MCL-1 levels have severe consequences in the context of hematopoietic recovery from stress.•Modulation of MCL-1 and PUMA is likely to reduce chemotherapy-associated toxicity and enhance blood stem cell transplantation in the clinic.
A common therapeutic strategy to combat human cancer is the use of combinations of drugs, each targeting different cellular processes or vulnerabilities. Recent studies suggest that addition of an ...MCL-1 inhibitor to such anticancer drug treatments could be an attractive therapeutic strategy. Thus, it is of great interest to understand whether combinations of conventional anticancer drugs with an MCL-1 inhibitor will be tolerable and efficacious. In order to mimic the combination of MCL-1 inhibition with other cancer therapeutics, we treated Mcl-1
heterozygous mice, which have a ~50% reduction in MCL-1 protein in their cells, with a broad range of chemotherapeutic drugs. Careful monitoring of treated mice revealed that a wide range of chemotherapeutic drugs had no significant effect on the general well-being of Mcl-1
mice with no overt damage to a broad range of tissues, including the haematopoietic compartment, heart, liver and kidney. These results indicate that MCL-1 inhibition may represent a tolerable strategy in cancer therapy, even when combined with select cytotoxic drugs.
Apoptotic cell death removes unwanted cells and is regulated by interactions between pro-survival and pro-apoptotic members of the BCL-2 protein family. The regulation of apoptosis is thought to be ...crucial for normal embryonic development. Accordingly, complete loss of pro-survival MCL-1 or BCL-XL (BCL2L1) causes embryonic lethality. However, it is not known whether minor reductions in pro-survival proteins could cause developmental abnormalities. We explored the rate-limiting roles of MCL-1 and BCL-XL in development and show that combined loss of single alleles of Mcl-1 and Bcl-x causes neonatal lethality. Mcl-1+/–;Bcl-x+/– mice display craniofacial anomalies, but additional loss of a single allele of pro-apoptotic Bim (Bcl2l11) restores normal development. These findings demonstrate that the control of cell survival during embryogenesis is finely balanced and suggest that some human craniofacial defects, for which causes are currently unknown, may be due to subtle imbalances between pro-survival and pro-apoptotic BCL-2 family members.
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•Control of embryonic cell survival by BCL-2 family proteins is finely balanced•Combined loss of single alleles of Mcl-1 and Bcl-x causes craniofacial defects•Loss of one allele of Bim restores normal development to Mcl-1+/−;Bcl-x+/− pups
Grabow et al. find that combined loss of single alleles of pro-survival Mcl-1 and Bcl-x causes craniofacial defects, including holoprosencephaly, a severe birth defect. Normal development is restored by concomitant loss of a single allele of pro-apoptotic Bim, revealing that cell survival and cell death during embryogenesis are finely balanced.
Combinations of chemotherapy with immunotherapy have seen recent clinical success, including two approvals of anti-PD-1/L1 agents in combination with taxane-based chemotherapy in non-small cell lung ...cancer and triple-negative breast cancer. Here, we present a study on the combination activity and mechanistic rationale of a novel EphA2-targeted liposomal taxane (EphA2-ILs-DTXp) and anti-PD-1. This combination was highly active in mouse syngeneic tumor models, with complete responses observed in 3 of 5 models. In the EMT-6 tumor model, combination of EphA2-ILs-DTXp with anti-PD-1 resulted in a 60% complete response rate, with durable responses that were resistant to rechallenge. These responses were not observed in the absence of CD8
T cells. Characterization of the immune infiltrates in EMT-6 tumors reveals increased CD8
T cells, increased CD8
IFNγ
CTLs, and an increased CD8/regulatory T-cell (Treg) ratio. These immunomodulatory effects were not observed in mice treated with a combination of docetaxel and anti-PD-1. Pharmacokinetic analysis revealed that the AUC of docetaxel was increased 15 times, from 52.1 to 785 ng/mL/hour, when delivered by EphA2-ILs-DTXp. A dose reduction study of EphA2-ILs-DTXp showed a dose-response relationship for both tumor growth inhibition and the CD8/Treg ratio. Our data indicate that synergism between docetaxel and anti-PD-1 is achievable with nanoliposomal delivery.
MCL-1 is critical for progenitor cell survival during emergency hematopoiesis, but its role in sustaining cells undergoing transformation and in lymphomagenesis is only poorly understood. We ...investigated the importance of MCL-1 in the survival of B lymphoid progenitors undergoing MYC-driven transformation and its functional interactions with pro-apoptotic BIM and PUMA and the tumor suppressor p53 in lymphoma development. Loss of one Mcl-1 allele almost abrogated MYC-driven-lymphoma development owing to a reduction in lymphoma initiating pre-B cells. Although loss of the p53 target PUMA had minor impact, loss of one p53 allele substantially accelerated lymphoma development when MCL-1 was limiting, most likely because p53 loss also causes defects in non-apoptotic tumor suppressive processes. Remarkably, loss of BIM restored the survival of lymphoma initiating cells and rate of tumor development. Thus, MCL-1 has a major role in lymphoma initiating pro-B cells to oppose BIM, which is upregulated in response to oncogenic stress.
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•Loss of one Mcl-1 allele substantially delays lymphomagenesis•MCL-1 antagonizes BIM in lymphoma development•Loss of p53 reduces requirement for MCL-1 during lymphomagenesis
MCL-1 is overexpressed in various human cancers. Grabow et al. reveal the importance of MCL-1 for the survival of B cell progenitors undergoing neoplastic transformation and in lymphomagenesis. Given that non-transformed cells appear to be less dependent on MCL-1 than malignant ones, inhibitors of MCL-1 may be useful in cancer therapy.
The histone acetyltransferase MOZ (MYST3, KAT6A) is the target of recurrent chromosomal translocations fusing the MOZ gene to CBP, p300, NCOA3, or TIF2 in particularly aggressive cases of acute ...myeloid leukemia. In this study, we report the role of wild-type MOZ in regulating B-cell progenitor proliferation and hematopoietic malignancy. In the Eμ-Myc model of aggressive pre-B/B-cell lymphoma, the loss of just one allele of Moz increased the median survival of mice by 3.9-fold. MOZ was required to maintain the proliferative capacity of B-cell progenitors, even in the presence of c-MYC overexpression, by directly maintaining the transcriptional activity of genes required for normal B-cell development. Hence, B-cell progenitor numbers were significantly reduced in Moz haploinsufficient animals. Interestingly, we find a significant overlap in genes regulated by MOZ, mixed lineage leukemia 1, and mixed lineage leukemia 1 cofactor menin. This includes Meis1, a TALE class homeobox transcription factor required for B-cell development, characteristically upregulated as a result of MLL1 translocations in leukemia. We demonstrate that MOZ localizes to the Meis1 locus in pre–B-cells and maintains Meis1 expression. Our results suggest that even partial inhibition of MOZ may reduce the proliferative capacity of MEIS1, and HOX-driven lymphoma and leukemia cells.
•Regulation of genes required for B-cell progenitor proliferation is exquisitely dependent on Moz gene dosage.•Loss of one Moz allele delays the onset of MYC-driven lymphoma by 3.9-fold.
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