Relative Mitochondrial Priming of Myeloblasts and Normal HSCs Determines Chemotherapeutic Success in AML

Vo, Thanh‐Trang; Ryan, Jeremy; Carrasco, Ruben D.; Neuberg, Donna; Rossi, Derrick J.; Stone, Richard; DeAngelo, Daniel J.; Frattini, Mark G.; Letaï, Anthony

doi:10.1016/j.cell.2012.08.038

Cited by 304 publications

(337 citation statements)

References 37 publications

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“…Bcl‐xl and Bcl‐2 increased in HUVECs, IMR90 cells, and MEFs but not preadipocytes, suggesting that senescent HUVECs, IMR90 cells, and MEFs might depend more on this pro‐survival pathway than N‐resistant preadipocytes. Consistent with this, Bcl‐2 family molecular signatures, including Bcl‐xl, Bcl‐2, Noxa, and Bcl‐w, correctly predict susceptibility to N of 70% of small‐cell lung cancers and 81% of leukemias and lymphomas (Tahir et al ., 2010; Vo et al ., 2012). These same Bcl‐2 family molecular signatures are features of senescent HUVECs, IMR90 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…N is senolytic in HUVECs, IMR90 cells, and MEFs, but not in senescent human primary preadipocytes. Based on these senescent cell type‐specific effects of N and its ability to treat cancers with specific Bcl‐2 family signatures (Tahir et al ., 2010; Vo et al ., 2012), we also tested signatures of Bcl‐2 family member proteins and found these signatures do indeed correlate with susceptibilities of different senescent cell types to N. This suggests that the molecular signatures of different types of senescent cells may be of utility in predicting responsiveness to Bcl‐2 family inhibitors or potentially to other classes of senolytic drugs.…”

Section: Introductionmentioning

confidence: 82%

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Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

et al. 2016

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SummaryClearing senescent cells extends healthspan in mice. Using a hypothesis‐driven bioinformatics‐based approach, we recently identified pro‐survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro‐survival regulators identified was Bcl‐xl. Here, we tested whether the Bcl‐2 family inhibitors, navitoclax (N) and TW‐37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl‐xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, T had little senolytic activity. N targets Bcl‐2, Bcl‐xl, and Bcl‐w, while T targets Bcl‐2, Bcl‐xl, and Mcl‐1. The combination of Bcl‐2, Bcl‐xl, and Bcl‐w siRNAs was senolytic in HUVECs and IMR90 cells, while combination of Bcl‐2, Bcl‐xl, and Mcl‐1 siRNAs was not. Susceptibility to N correlated with patterns of Bcl‐2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to N. Thus, N is senolytic and acts in a potentially predictable cell type‐restricted manner. The hypothesis‐driven, bioinformatics‐based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type‐specific senolytic agents.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 82%

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

et al. 2016

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“…[39][40][41][42] In particular, the present study utilizes full-length BH3-only proteins, which differ in the strengths of their protein-protein interactions compared with isolated BH3 peptides, 49 and places those BH3-only proteins in the context of cellular signaling networks 2,45 rather than isolated mitochondria. Thus, although BH3 profiling is being explored as a strategy to predict sensitivity or resistance of particular cell lines or cancers to specific treatments, 50 measurement of BH3-only tolerance has the potential to provide insight into endogenous signaling networks within intact cells that include BCL2 family members bound to surfaces other than the MOM.…”

Section: Discussionmentioning

confidence: 99%

“…41,42 This assay involves treating mitochondria or permeabilized cells with isolated BH3 peptides and measuring cytochrome c release or mitochondrial depolarization. In a recent modification termed 'dynamic BH3 profiling,' cells are exposed to potential anticancer drugs versus diluent and assayed for BIM BH3 peptideinduced mitochondrial depolarization.…”

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confidence: 99%

Measurement of BH3-only protein tolerance

et al. 2017

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The BCL2 family of proteins regulates cellular life and death decisions. Among BCL2 family members, BH3-only proteins have critical roles by neutralizing antiapoptotic family members, as well as directly activating BAX and BAK. Despite widespread occurrence of BH3-only protein upregulation in response to various stresses, this process is rarely quantified. Moreover, it is unclear whether all BH3-only proteins are equipotent at inducing cell death. Here we show that BH3-only proteins increase as much as 15-to 20-fold after various treatments and define a parameter, termed BH3-only tolerance, which measures how many copies of a particular BH3-only protein can be expressed before the majority of cells in a population undergo apoptosis. We not only assess the relative contributions of anti-and proapoptotic BCL2 family members to BH3-only tolerance, but also illustrate how the study of this parameter can be used to understand cellular sensitivity to anticancer drugs and new combinations. These observations provide a new quantitative framework for assessing apoptotic susceptibility under various conditions.

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“…This property correlates with the success of clinical induction and refines the prognostic information obtained from cytogenetic and genetic markers. Furthermore, chemosensitive and chemoresistant myeloblasts but not normal hematopoietic stem cells (HSCs) showed BCL-2 dependency in BH3 profiling [26]. This provides the basis for the use of BCL-2 antagonists for the development of new therapeutic strategies for treating AML patients.…”

Section: Drugs Targeting Bcl-2 Protein Familymentioning

confidence: 99%

Targeting the mitochondria in acute myeloid leukemia

Sánchez-Mendoza

Rego

2017

Appl Cancer Res

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Acute myeloid leukemia (AML) is a clonal hematologic neoplasm characterized by heterogeneity of genetic abnormalities found at diagnosis. These abnormalities serve to classify patients by risk group into low, intermediate, and high risk. It also provides specific targets for the development of new combinational therapies. However, because of the heterogeneity of genetic abnormalities, targeted therapy is not always possible. Altered mitochondrial metabolism is a common feature in cancer cells, a phenomenon first described by Otto Warburg. In AML patients, the discovery of mutations in the isocitrate dehydrogenase gene provided for the first time a link between altered mitochondrial metabolism and AML. This raised the possibility of testing drugs known as mitocans for new combinational therapeutic approaches. Mitocans are a diverse group of anti-cancer compounds that target mitochondria. They disrupt energy production leading to enhanced generation of reactive oxygen species along with the activation of the intrinsic pathway of apoptosis. The present review discusses the different types of mitocans and their mechanism of action along with preclinical and clinical studies in AML.

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Relative Mitochondrial Priming of Myeloblasts and Normal HSCs Determines Chemotherapeutic Success in AML

Cited by 304 publications

References 37 publications

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

Measurement of BH3-only protein tolerance

Targeting the mitochondria in acute myeloid leukemia

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