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22 pages, 8056 KiB

Open AccessArticle

Deciphering the Role of Pyrvinium Pamoate in the Generation of Integrated Stress Response and Modulation of Mitochondrial Function in Myeloid Leukemia Cells through Transcriptome Analysis

by Yu-Hsuan Fu, Chi-Yang Tseng, Jeng-Wei Lu, Wen-Hui Lu, Pei-Qi Lan, Chien-Yuan Chen, Da-Liang Ou and Liang-In Lin

Biomedicines 2021, 9(12), 1869; https://doi.org/10.3390/biomedicines9121869 - 9 Dec 2021

Cited by 5 | Viewed by 3670

Abstract

Pyrvinium pamoate, a widely-used anthelmintic agent, reportedly exhibits significant anti-tumor effects in several cancers. However, the efficacy and mechanisms of pyrvinium against myeloid leukemia remain unclear. The growth inhibitory effects of pyrvinium were tested in human AML cell lines. Transcriptome analysis of Molm13 [...] Read more.

Pyrvinium pamoate, a widely-used anthelmintic agent, reportedly exhibits significant anti-tumor effects in several cancers. However, the efficacy and mechanisms of pyrvinium against myeloid leukemia remain unclear. The growth inhibitory effects of pyrvinium were tested in human AML cell lines. Transcriptome analysis of Molm13 myeloid leukemia cells suggested that pyrvinium pamoate could trigger an unfolded protein response (UPR)-like pathway, including responses to extracellular stimulus [p-value = 2.78 × 10⁻⁶] and to endoplasmic reticulum stress [p-value = 8.67 × 10⁻⁷], as well as elicit metabolic reprogramming, including sulfur compound catabolic processes [p-value = 2.58 × 10⁻⁸], and responses to a redox state [p-value = 5.80 × 10⁻⁵]; on the other hand, it could elicit a pyrvinium blunted protein folding function, including protein folding [p-value = 2.10 × 10⁻⁸] and an ATP metabolic process [p-value = 3.95 × 10⁻⁴]. Subsequently, pyrvinium was verified to induce an integrated stress response (ISR), demonstrated by activation of the eIF2α-ATF4 pathway and inhibition of mTORC1 signaling, in a dose- and time-dependent manner. Additionally, pyrvinium could co-localize with mitochondria and then decrease the mitochondrial basal oxidative consumption rate, ultimately dysregulating the mitochondrial function. Similar effects were observed in cabozantinib-resistant Molm13-XR cell lines. Furthermore, pyrvinium treatment retarded Molm13 and Molm13-XR xenograft tumor growth. Thus, we concluded that pyrvinium exerts anti-tumor activity, at least, via the modulation of the mitochondrial function and by triggering ISR. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: From Pathophysiology to Novel Therapeutic Approaches)

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8 pages, 718 KiB

Open AccessArticle

Hypomethylating Agents (HMAs) as Salvage Therapy in Relapsed or Refractory AML: An Italian Multicentric Retrospective Study

by Federica Lessi, Marica Laurino, Cristina Papayannidis, Orsola Vitagliano, Francesco Grimaldi, Davide Lazzarotto, Michele Gottardi, Elena Crisà, Marta Riva, Gianluigi Reda, Mario Ermani, Gianpietro Semenzato, Livio Trentin and Felicetto Ferrara

Biomedicines 2021, 9(8), 972; https://doi.org/10.3390/biomedicines9080972 - 6 Aug 2021

Cited by 4 | Viewed by 1701

Abstract

Data on the use of azacytidine and decitabine as salvage therapy for acute myeloid leukemia are limited. We retrospectively reviewed clinical records of 100 patients treated with hypomethylating agents (HMA) as salvage therapy in nine Italian institutions. A total of 24% of patients [...] Read more.

Data on the use of azacytidine and decitabine as salvage therapy for acute myeloid leukemia are limited. We retrospectively reviewed clinical records of 100 patients treated with hypomethylating agents (HMA) as salvage therapy in nine Italian institutions. A total of 24% of patients obtained a response to HMA (CR, PR, or CRi), while 26% showed a stable disease (SD); 50% of patients experienced progressive disease. Median OS was 6.5 months. OS in patients with de novo AML was 6.1 months, while OS in patients with secondary AML (sAML) was 12.3 months (p = 0.037). Median OS after HMA in patients with SD as best response to HMA was similar to median OS in patients with response to HMA (10.6 months vs. 13 months). On multivariate analysis, OS difference between patients who obtained a response versus patients who did not was significant (p = 0.0037). OS difference in sAML was significantly better than in de novo AML (p < 0.00001). HMA showed a remarkable efficacy in terms of response rate and OS in a subgroup of patients (sAMLs), historically characterized by a poor outcome. Therefore, 5Azacitidine and decitabine may represent a good clinical option in a selected patient population with relapsed or refractory AML, unsuitable for allo-HSCT. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: From Pathophysiology to Novel Therapeutic Approaches)

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19 pages, 3919 KiB

Open AccessArticle

Pharmacological Inhibition of WIP1 Sensitizes Acute Myeloid Leukemia Cells to the MDM2 Inhibitor Nutlin-3a

by Maria Chiara Fontana, Jacopo Nanni, Andrea Ghelli Luserna di Rorà, Elisabetta Petracci, Antonella Padella, Martina Ghetti, Anna Ferrari, Giovanni Marconi, Simona Soverini, Ilaria Iacobucci, Cristina Papayannidis, Antonio Curti, Ernesta Audisio, Maria Benedetta Giannini, Michela Rondoni, Francesco Lanza, Michele Cavo, Giovanni Martinelli and Giorgia Simonetti

Biomedicines 2021, 9(4), 388; https://doi.org/10.3390/biomedicines9040388 - 6 Apr 2021

Cited by 7 | Viewed by 3727

Abstract

In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in combinatorial therapies. WIP1, encoded from PPM1D, is a negative regulator of p53. We evaluated PPM1D expression and explored the therapeutic efficacy of WIP1 inhibitor (WIP1i) GSK2830371, [...] Read more.

In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in combinatorial therapies. WIP1, encoded from PPM1D, is a negative regulator of p53. We evaluated PPM1D expression and explored the therapeutic efficacy of WIP1 inhibitor (WIP1i) GSK2830371, in association with the MDM2 inhibitor Nutlin-3a (Nut-3a) in AML cell lines and primary samples. PPM1D transcript levels were higher in young patients compared with older ones and in core-binding-factor AML compared with other cytogenetic subgroups. In contrast, its expression was reduced in NPM1-mutated (mut, irrespective of FLT3-ITD status) or TP53-mut cases compared with wild-type (wt) ones. Either Nut-3a, and moderately WIP1i, as single agent decreased cell viability of TP53-wt cells (MV-4-11, MOLM-13, OCI-AML3) in a time/dosage-dependent manner, but not of TP53-mut cells (HEL, KASUMI-1, NOMO-1). The drug combination synergistically reduced viability and induced apoptosis in TP53-wt AML cell line and primary cells, but not in TP53-mut cells. Gene expression and immunoblotting analyses showed increased p53, MDM2 and p21 levels in treated TP53-wt cells and highlighted the enrichment of MYC, PI3K-AKT-mTOR and inflammation-related signatures upon WIP1i, Nut-3a and their combination, respectively, in the MV-4-11 TP53-wt model. This study demonstrated that WIP1 is a promising therapeutic target to enhance Nut-3a efficacy in TP53-wt AML. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: From Pathophysiology to Novel Therapeutic Approaches)

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14 pages, 1421 KiB

Open AccessArticle

WT1 Expression Levels Combined with Flow Cytometry Blast Counts for Risk Stratification of Acute Myeloid Leukemia and Myelodysplastic Syndromes

by Valentina Giudice, Marisa Gorrese, Rosa Vitolo, Angela Bertolini, Rossella Marcucci, Bianca Serio, Roberto Guariglia, Idalucia Ferrara, Rita Pepe, Francesca D’Alto, Barbara Izzo, Antonio Pedicini, Nunzia Montuori, Maddalena Langella and Carmine Selleri

Biomedicines 2021, 9(4), 387; https://doi.org/10.3390/biomedicines9040387 - 6 Apr 2021

Cited by 11 | Viewed by 3192

Abstract

Wilm’s tumor 1 (WT1), a zinc-finger transcription factor and an epigenetic modifier, is frequently overexpressed in several hematologic disorders and solid tumors, and it has been proposed as diagnostic and prognostic marker of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). [...] Read more.

Wilm’s tumor 1 (WT1), a zinc-finger transcription factor and an epigenetic modifier, is frequently overexpressed in several hematologic disorders and solid tumors, and it has been proposed as diagnostic and prognostic marker of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the exact role of WT1 in leukemogenesis and disease progression remains unclear. In this real-world evidence retrospective study, we investigated prognostic role of WT1-mRNA expression levels in AML and MDS patients and correlations with complete blood counts, flow cytometry counts, and molecular features. A total of 71 patients (AML, n = 46; and MDS, n = 25) were included in this study, and WT1 levels were assessed at diagnosis, during treatment and follow-up. We showed that WT1 expression levels were inversely correlated with normal hemopoiesis in both AML and MDS, and positively associated with blast counts. Flow cytometry was more sensitive and specific in distinguishing normal myeloid cells from neoplastic counterpart even just using linear parameters and CD45 expression. Moreover, we showed that a simple integrated approach combining blast counts by flow cytometry, FLT3 mutational status, and WT1 expression levels might be a useful tool for a better prognostic definition in both AML and MDS patients. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: From Pathophysiology to Novel Therapeutic Approaches)

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Review

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18 pages, 354 KiB

Open AccessReview

High-Risk Acute Myeloid Leukemia: A Pediatric Prospective

by Fabiana Cacace, Rossella Iula, Danilo De Novellis, Valeria Caprioli, Maria Rosaria D’Amico, Giuseppina De Simone, Rosanna Cuccurullo, William G. Wierda, Kris Michael Mahadeo, Giuseppe Menna and Francesco Paolo Tambaro

Biomedicines 2022, 10(6), 1405; https://doi.org/10.3390/biomedicines10061405 - 14 Jun 2022

Cited by 3 | Viewed by 2778

Abstract

Pediatric acute myeloid leukemia is a clonal disorder characterized by malignant transformation of the hematopoietic stem cell. The incidence and the outcome remain inferior when compared to pediatric ALL, although prognosis has improved in the last decades, with 80% overall survival rate reported [...] Read more.

Pediatric acute myeloid leukemia is a clonal disorder characterized by malignant transformation of the hematopoietic stem cell. The incidence and the outcome remain inferior when compared to pediatric ALL, although prognosis has improved in the last decades, with 80% overall survival rate reported in some studies. The standard therapeutic approach is a combined cytarabine and anthracycline-based regimen followed by consolidation with allogeneic stem cell transplantation (allo-SCT) for high-risk AML and allo-SCT for non-high-risk patients only in second complete remission after relapse. In the last decade, several drugs have been used in clinical trials to improve outcomes in pediatric AML treatment. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: From Pathophysiology to Novel Therapeutic Approaches)

22 pages, 3000 KiB

Open AccessReview

The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia

by Bernhard Moser, Sophie Edtmayer, Agnieszka Witalisz-Siepracka and Dagmar Stoiber

Biomedicines 2021, 9(8), 1051; https://doi.org/10.3390/biomedicines9081051 - 19 Aug 2021

Cited by 13 | Viewed by 6648

Abstract

Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival [...] Read more.

Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival rates in the elderly have not shown a substantial improvement over the past decades. This is particularly due to the heterogeneity of AML and the need for personalized approaches. Due to the crucial role of the deregulated JAK-STAT signaling in AML, selective targeting of the JAK-STAT pathway, particularly constitutively activated STAT3 and STAT5 and their associated upstream JAKs, is of great interest. This strategy has shown promising results in vitro and in vivo with several compounds having reached clinical trials. Here, we summarize recent FDA approvals and current potential clinically relevant inhibitors for AML patients targeting JAK and STAT proteins. This review underlines the need for detailed cytogenetic analysis and additional assessment of JAK-STAT pathway activation. It highlights the ongoing development of new JAK-STAT inhibitors with better disease specificity, which opens up new avenues for improved disease management. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: From Pathophysiology to Novel Therapeutic Approaches)

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30 pages, 429 KiB

Open AccessReview

How to Improve Prognostication in Acute Myeloid Leukemia with CBFB-MYH11 Fusion Transcript: Focus on the Role of Molecular Measurable Residual Disease (MRD) Monitoring

by Annalisa Talami, Francesca Bettelli, Valeria Pioli, Davide Giusti, Andrea Gilioli, Corrado Colasante, Laura Galassi, Rachele Giubbolini, Hillary Catellani, Francesca Donatelli, Rossana Maffei, Silvia Martinelli, Patrizia Barozzi, Leonardo Potenza, Roberto Marasca, Tommaso Trenti, Enrico Tagliafico, Patrizia Comoli, Mario Luppi and Fabio Forghieri

Biomedicines 2021, 9(8), 953; https://doi.org/10.3390/biomedicines9080953 - 3 Aug 2021

Cited by 5 | Viewed by 3597

Abstract

Acute myeloid leukemia (AML) carrying inv(16)/t(16;16), resulting in fusion transcript CBFB-MYH11, belongs to the favorable-risk category. However, even if most patients obtain morphological complete remission after induction, approximately 30% of cases eventually relapse. While well-established clinical features and concomitant cytogenetic/molecular lesions have [...] Read more.

Acute myeloid leukemia (AML) carrying inv(16)/t(16;16), resulting in fusion transcript CBFB-MYH11, belongs to the favorable-risk category. However, even if most patients obtain morphological complete remission after induction, approximately 30% of cases eventually relapse. While well-established clinical features and concomitant cytogenetic/molecular lesions have been recognized to be relevant to predict prognosis at disease onset, the independent prognostic impact of measurable residual disease (MRD) monitoring by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR), mainly in predicting relapse, actually supersedes other prognostic factors. Although the ELN Working Party recently indicated that patients affected with CBFB-MYH11 AML should have MRD assessment at informative clinical timepoints, at least after two cycles of intensive chemotherapy and after the end of treatment, several controversies could be raised, especially on the frequency of subsequent serial monitoring, the most significant MRD thresholds (most commonly 0.1%) and on the best source to be analyzed, namely, bone marrow or peripheral blood samples. Moreover, persisting low-level MRD positivity at the end of treatment is relatively common and not predictive of relapse, provided that transcript levels remain stably below specific thresholds. Rising MRD levels suggestive of molecular relapse/progression should thus be confirmed in subsequent samples. Further prospective studies would be required to optimize post-remission monitoring and to define effective MRD-based therapeutic strategies. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: From Pathophysiology to Novel Therapeutic Approaches)

15 pages, 23115 KiB

Open AccessReview

RSK Isoforms in Acute Myeloid Leukemia

by Minyoung Youn, Jesus Omar Gomez, Kailen Mark and Kathleen M. Sakamoto

Biomedicines 2021, 9(7), 726; https://doi.org/10.3390/biomedicines9070726 - 24 Jun 2021

Cited by 10 | Viewed by 5011

Abstract

Ribosomal S6 Kinases (RSKs) are a group of serine/threonine kinases that function downstream of the Ras/Raf/MEK/ERK signaling pathway. Four RSK isoforms are directly activated by ERK1/2 in response to extracellular stimuli including growth factors, hormones, and chemokines. RSKs phosphorylate many cytosolic and nuclear [...] Read more.

Ribosomal S6 Kinases (RSKs) are a group of serine/threonine kinases that function downstream of the Ras/Raf/MEK/ERK signaling pathway. Four RSK isoforms are directly activated by ERK1/2 in response to extracellular stimuli including growth factors, hormones, and chemokines. RSKs phosphorylate many cytosolic and nuclear targets resulting in the regulation of diverse cellular processes such as cell proliferation, survival, and motility. In hematological malignancies such as acute myeloid leukemia (AML), RSK isoforms are highly expressed and aberrantly activated resulting in poor outcomes and resistance to chemotherapy. Therefore, understanding RSK function in leukemia could lead to promising therapeutic strategies. This review summarizes the current information on human RSK isoforms and discusses their potential roles in the pathogenesis of AML and mechanism of pharmacological inhibitors. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: From Pathophysiology to Novel Therapeutic Approaches)

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