Multi-sites cleavage of leukemogenic AML1-ETO fusion protein by caspase-3 and its contribution to increased apoptotic sensitivity

Lu, Yiming; Zg, Peng; Tt, Yuan; Qq, Yin; Xia, Ling; Gq, Chen

doi:10.1038/sj.leu.2405020

Cited by 24 publications

(31 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It was also found that the addition of methotrexate almost completely blocked the nuclear translocation of DHFR protein while it failed to impinge on the apoptosis induction [59] . Moreover, using leukemic cell apoptosis induced by NSC606985 and other chemotherapeutic agents as a model, we confirmed that PU.1 [60] (one of the key regulators of hematopoietic cell development) and leukemia-associated fusion protein AML1-ETO [61] are direct substrates of the apoptosis executioner caspase-3 and their target sites for caspase-3 cleavage have been identified by site-directed mutagenesis. Lastly, the conditional induction of AML1-ETO is shown to endow leukemic cells with the susceptibility to anti-Fas agonist antibody, ultraviolet light, and NSC6069 85-induced apoptosis [62] .…”

Section: Discoveries About Cell Apoptosis Induction Based On Small Mosupporting

confidence: 61%

Active compounds-based discoveries about the differentiation and apoptosis of leukemic cells

2009

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignancies which are characterized by the blockage of hematopoietic cell differentiation with uncontrolled proliferation and/or impaired apoptosis. Over the past 20 years, there has been tremendous progress in the biological, molecular, and cytogenetic aspects of the disease, accompanied by significant advancements in the treatment of AML patients. For example, all-trans retinoic acid (ATRA) and arsenic trioxide (As 2 O 3 ) have been used clinically for effective treatments of patients with acute promyelocytic leukemia (APL, a unique subtype of AML) through differentiation and/or apoptosis induction. More intriguingly, these active compounds-based chemical biological studies greatly accelerated our understanding on leukemogenesis and targeted therapy of AML patients. Based on some recent findings mainly from our group, this review attempts to summarize the related advances from Chinese researchers. chemical biology, leukemia, cell differentiation, apoptosis Acute myeloid leukemia (AML), a heterogeneous group of hematopoietic malignancies, occurs frequently in adults. Remarkable advances in the biological, molecular and cytogenetic aspects of this disease have been made over the past 20 years. It is well-established that specific cytogenetic alterations, particularly chromosomal translocations that generate abnormal oncogenic fusion proteins, such as t(15;17) yielding PML-RARα (promyelocytic leukemia-retinoic acid receptor-alpha) and t(8;21) yielding AML1-ETO (acute myeloid leukemia 1-eight twenty-one), cause the blockage of hematopoietic cell differentiation at a certain stage, accompanied by uncontrolled proliferation and/or impaired apoptosis. On the other hand, the past decades are also marked by great advances in the treatment of AML patients. One typical example is the discovery that all-trans retinoic acid (ATRA) and arsenic trioxide (As 2 O 3 ) could effectively treat patients with acute promyelocytic leukemia (APL, also known as M3-type AML) through the induction of differentiation and/or apoptosis. Due to the relative convenience of acquiring leukemia samples and the ease of the evaluation of therapeutic effects, chemical biological methodologies that use specific, active small molecules (such as ATRA and As 2 O 3 ) as probes to investigate mechanisms of basic cellular activities greatly accelerated our understanding of leukemogenesis and targeted therapy of AML patients [1] . Based on some recent findings primarily from our group, this review attempts to summarize the related advances from Chinese researchers.

show abstract

Section: Discoveries About Cell Apoptosis Induction Based On Small Mosupporting

confidence: 61%

Active compounds-based discoveries about the differentiation and apoptosis of leukemic cells

2009

View full text Add to dashboard Cite

show abstract

“…28,31 Because both VPA and vorinostat induced cleavage of pro-caspase-3 and PARP, concomitant with the loss of AML1-ETO ( Figures 1A and 2A-B), we next tested whether caspases were involved in drug-induced AML1-ETO catabolism. Indeed, blocking caspase activity with the pan-caspase inhibitor zVAD-fmk efficiently reversed drug-induced loss of AML1-ETO ( Figure 2F; supplemental Figure 4).…”

Section: Blood 3 October 2013 X Volume 122 Number 14 Autophagy Is Pmentioning

confidence: 99%

Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells

Torgersen

Engedal

Bøe

et al. 2013

Blood

View full text Add to dashboard Cite

Key Points• In AML1-ETO-positive AML cells, HDAC inhibitors induce autophagy, which acts as a prosurvival signal to limit HDAC-induced cell death.• In contrast to the fusion oncoproteins PML-RARA and breakpoint cluster regionabelson, AML1-ETO is not degraded by either basal-or drug-induced autophagy.The role of autophagy during leukemia treatment is unclear. On the one hand, autophagy might be induced as a prosurvival response to therapy, thereby reducing treatment efficiency. On the other hand, autophagy may contribute to degradation of fusion oncoproteins, as recently demonstrated for promyelocytic leukemia-retinoic acid receptor a and breakpoint cluster region-abelson, thereby facilitating leukemia treatment. Here, we investigated these opposing roles of autophagy in t(8;21) acute myeloid leukemia (AML) cells, which express the most frequently occurring AML fusion oncoprotein, AML1-eight-twenty-one (ETO). We demonstrate that autophagy is induced by AML1-ETO-targeting drugs, such as the histone deacetylase inhibitors (HDACis) valproic acid (VPA) and vorinostat. Furthermore, we show that autophagy does not mediate degradation of AML1-ETO but rather has a prosurvival role in AML cells, as inhibition of autophagy significantly reduced the viability and colony-forming ability of HDACi-treated AML cells. Combined treatment with HDACis and autophagy inhibitors such as chloroquine (CQ) led to a massive accumulation of ubiquitinated proteins that correlated with increased cell death. Finally, we show that VPA induced autophagy in t(8;21) AML patient cells, and combined treatment with CQ enhanced cell death. Because VPA and CQ are well-tolerated drugs, combinatorial therapy with VPA and CQ could represent an attractive treatment option for AML1-ETO-positive leukemia. (Blood. 2013;122(14):2467-2476) IntroductionMacroautophagy, hereafter referred to as autophagy, is a catabolic pathway that is upregulated during times of nutrient limitations or stress to maintain cellular metabolism and organelle integrity. 1Autophagy involves sequestration of cytoplasmic cargo, such as long-lived proteins, damaged organelles, and protein aggregates, into double-membrane vesicles termed autophagosomes, which fuse with lysosomes, leading to degradation of the contents by acidic hydrolases. 1 There is currently a pressing need to understand in which settings autophagy should be inhibited and in which instances autophagy should be activated, to overcome drug resistance and optimize cancer treatment. Recent studies indicate that anticancer treatment may be hampered by the activation of autophagy as a prosurvival mechanism that prevents apoptosis and delays necrosis in the cancer cells. 2,3 Thus, including autophagy inhibitors in cancer therapy could potentially overcome cancer drug resistance. 4,5 However, autophagy has also been suggested to be a mediator of cell death in certain contexts, 6 and it was recently demonstrated that autophagy facilitates basal and therapy-induced degradation of promyelocytic leukemia-retinoic acid receptor a (P...

show abstract

“…On the other hand, our preliminary experiments showed that higher concentrations of adenanthin can induce AML cell lines to undergo cell death in vitro, which was associated with significantly elevated H 2 O 2 (data not shown). Previously, we showed that inducible expression of AML1-ETO, a leukemiaassociated fusion protein generated by the frequently occurred chromosome translocation t(8;21) in AML, endows leukemic cells with susceptibility to extrinsic and intrinsic apoptosis [40], and it can be cleaved on multiple sites by caspase-3 [41]. More recently, oridonin is shown to interact with glutathione and thioredoxin/thioredoxin reductase to increase intracellular ROS, which in turn activate caspase-3 in AML with the t(8;21) translocation, while a truncated AML1-ETO by caspase-3 interacts with AML1-ETO and interferes with the trans-regulatory functions of remaining AML1-ETO oncoprotein, thus acting as a tumor suppressor that mediates the anti-leukemia effect of oridonin [42].…”

Section: Future Perspectivementioning

confidence: 99%

Targeting peroxiredoxins against leukemia

Liu

Zhou

Yin

et al. 2013

Experimental Cell Research

View full text Add to dashboard Cite

Multi-sites cleavage of leukemogenic AML1-ETO fusion protein by caspase-3 and its contribution to increased apoptotic sensitivity

Cited by 24 publications

References 39 publications

Active compounds-based discoveries about the differentiation and apoptosis of leukemic cells

Active compounds-based discoveries about the differentiation and apoptosis of leukemic cells

Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells

Targeting peroxiredoxins against leukemia

Contact Info

Product

Resources

About