Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure

Pandolfi, Pier Paolo; Zhu, Chen

doi:10.1016/j.ccell.2017.10.002

Cited by 243 publications

(203 citation statements)

References 128 publications

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“…SUMOylation of PML recruits RNF4 and triggers its degradation in a ubiquitination-proteasome-dependent way. [106][107][108] Therefore, SUMOylation takes part in a variety of cellular physiological activities, such as gene stability maintenance and transcriptional regulation, and aberrant SUMOylation is closely related to the development and progression of certain diseases, including cancer.…”

Section: Ub-like Proteinsmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

468

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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Section: Ub-like Proteinsmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

468

308

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“…Multiple other features of PML-RARA were described, but their actual contributions to in vivo transformation remains unestablished. One of the most striking features of APL is its sensitivity to targeted therapies [6]. Indeed, APL has now become the most curable form of adult leukemia when treated by combined therapies with all trans-retinoic acid (ATRA) and arsenic trioxide (ATO).…”

Section: Current Understanding Of Classic Apl Pathogenesis and Treatmmentioning

confidence: 99%

“…Thus, ATRA and ATO are targeted therapies directed onto the two constitutive moieties of the PML-RARA fusion. The dual targeting of PML-RARA (for destruction) and PML (for NB formation prior to catabolism) explains the potency of single agent arsenic for APL [6,38].…”

Section: Current Understanding Of Classic Apl Pathogenesis and Treatmmentioning

confidence: 99%

“…The resulting chimeric PML-RARA protein ( Figure 1) promotes a clonal proliferation of myeloid precursors with a reduced differentiation capacity and acquisition of self-renewal. Pathogenesis of these "classic" APLs has been extensively reviewed elsewhere [6][7][8] and will only be sketched here. The World Health Organization (WHO) has revised the classification of AMLs, making APL with t(15; 17) (q24.1; q21.2), as a specific entity, but without taking in account the novel PML-independent RARs fusions [9].…”

Section: Introductionmentioning

confidence: 99%

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Classic and Variants APLs, as Viewed from a Therapy Response

Geoffroy

2020

Cancers

Self Cite

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Most acute promyelocytic leukemia (APL) are caused by PML-RARA, a translocation-driven fusion oncoprotein discovered three decades ago. Over the years, several other types of rare X-RARA fusions have been described, while recently, oncogenic fusion proteins involving other retinoic acid receptors (RARB or RARG) have been associated to very rare cases of acute promyelocytic leukemia. PML-RARA driven pathogenesis and the molecular basis for therapy response have been the focus of many studies, which have now converged into an integrated physio-pathological model. The latter is well supported by clinical and molecular studies on patients, making APL one of the rare hematological disorder cured by targeted therapies. Here we review recent data on APL-like diseases not driven by the PML-RARA fusion and discuss these in view of current understanding of “classic” APL pathogenesis and therapy response.

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“…Experimental strategies for the treatment of resistant APL Treatment outcomes in patients with newly diagnosed APL have improved dramatically in the last three decades since the advent of ATRA and, some years later, the introduction of ATO -ATRA combined with chemotherapy resulted in cure rates above 80%; but was associated with the risk of severe infections and secondary leukemias [98][99][100][101]. ATO has been shown to act synergistically with ATRA to induce the degradation of the PML-RARΑ oncoprotein [102] and the chemo-free ATRA-ATO approach is nowadays regarded as the first treatment choice for patients with nonhigh-risk APL [71,72,103]. A recent review from the European leukemia network details the guidelines in the management of frontline and relapsed APL and the specific recommendations for the identification and management of the most important complications: bleeding disorder, differentiation syndrome, QT prolongation and all the other toxicities related to treatment with ATRA and ATO [55] When diagnosed and treated promptly, APL is curable in the vast majority of patients, yet approximately 5 % of cases are resistant to standard therapy and 5 to 10% relapse and eventually become resistant (Coombs et al 2015).…”

mentioning

confidence: 99%

Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies

Noguera

Catalano

Banella

et al. 2019

Preprint

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In this review, we highlight new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in APL. PML-RARa sets the cellular landscape of Acute promyelocytic leukemia (APL) by repressing transcription of RARa target genes and disrupting PML-NBs. RAR receptors control the homeostasis of tissue growth, modeling and regeneration, PML NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. Additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. Treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. Resistance to ATRA and ATO may derive from mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5-10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or induction of apoptosis in APL cells.

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Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure

Cited by 243 publications

References 128 publications

The role of ubiquitination in tumorigenesis and targeted drug discovery

The role of ubiquitination in tumorigenesis and targeted drug discovery

Classic and Variants APLs, as Viewed from a Therapy Response

Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies

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