Research

12 pages, 1456 KiB

Open AccessArticle

A Combination of the Immunotherapeutic Drug Anti-Programmed Death 1 with Lenalidomide Enhances Specific T Cell Immune Responses against Acute Myeloid Leukemia Cells

by Barbara-ann Guinn, Patrick J. Schuler, Hubert Schrezenmeier, Susanne Hofmann, Johanna Weiss, Christiane Bulach, Marlies Götz and Jochen Greiner

Int. J. Mol. Sci. 2023, 24(11), 9285; https://doi.org/10.3390/ijms24119285 - 26 May 2023

Cited by 2 | Viewed by 1524

Abstract

Immune checkpoint inhibitors can block inhibitory molecules on the surface of T cells, switching them from an exhausted to an active state. One of these inhibitory immune checkpoints, programmed cell death protein 1 (PD-1) is expressed on T cell subpopulations in acute myeloid [...] Read more.

Immune checkpoint inhibitors can block inhibitory molecules on the surface of T cells, switching them from an exhausted to an active state. One of these inhibitory immune checkpoints, programmed cell death protein 1 (PD-1) is expressed on T cell subpopulations in acute myeloid leukemia (AML). PD-1 expression has been shown to increase with AML progression following allo-haematopoeitic stem cell transplantation, and therapy with hypomethylating agents. We have previously shown that anti-PD-1 can enhance the response of leukemia-associated antigen (LAA)-specific T cells against AML cells as well as leukemic stem and leukemic progenitor cells (LSC/LPCs) ex vivo. In concurrence, blocking of PD-1 with antibodies such as nivolumab has been shown to enhance response rates post-chemotherapy and stem cell transplant. The immune modulating drug lenalidomide has been shown to promote anti-tumour immunity including anti-inflammatory, anti-proliferative, pro-apoptotic and anti-angiogenicity. The effects of lenalidomide are distinct from chemotherapy, hypomethylating agents or kinase inhibitors, making lenalidomide an attractive agent for use in AML and in combination with existing active agents. To determine whether anti-PD-1 (nivolumab) and lenalidomide alone or in combination could enhance LAA-specific T cell immune responses, we used colony-forming immune and ELISpot assays. Combinations of immunotherapeutic approaches are believed to increase antigen-specific immune responses against leukemic cells including LPC/LSCs. In this study we used a combination of LAA-peptides with the immune checkpoint inhibitor anti-PD-1 and lenalidomide to enhance the killing of LSC/LPCs ex vivo. Our data offer a novel insight into how we could improve AML patient responses to treatment in future clinical studies. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia 2.0)

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22 pages, 5747 KiB

Open AccessArticle

Combination Therapies Targeting Apoptosis in Paediatric AML: Understanding the Molecular Mechanisms of AML Treatments Using Phosphoproteomics

by Ahlam A. Ali, Lauren V. Cairns, Kathryn M. Clarke, Jaine K. Blayney, Katrina M. Lappin and Ken I. Mills

Int. J. Mol. Sci. 2023, 24(6), 5717; https://doi.org/10.3390/ijms24065717 - 16 Mar 2023

Viewed by 1717

Abstract

Paediatric acute myeloid leukaemia (AML) continues to present treatment challenges, as no “standard approach” exists to treat those young patients reliably and safely. Combination therapies could become a viable treatment option for treating young patients with AML, allowing multiple pathways to be targeted. [...] Read more.

Paediatric acute myeloid leukaemia (AML) continues to present treatment challenges, as no “standard approach” exists to treat those young patients reliably and safely. Combination therapies could become a viable treatment option for treating young patients with AML, allowing multiple pathways to be targeted. Our in silico analysis of AML patients highlighted “cell death and survival” as an aberrant, potentially targetable pathway in paediatric AML patients. Therefore, we aimed to identify novel combination therapies to target apoptosis. Our apoptotic drug screening resulted in the identification of one potential “novel” drug pairing, comprising the Bcl-2 inhibitor ABT-737 combined with the CDK inhibitor Purvalanol-A, as well as one triple combination of ABT-737 + AKT inhibitor + SU9516, which showed significant synergism in a series of paediatric AML cell lines. Using a phosphoproteomic approach to understand the apoptotic mechanism involved, proteins related to apoptotic cell death and cell survival were represented, in agreement with further results showing differentially expressed apoptotic proteins and their phosphorylated forms among combination treatments compared to single-agent treated cells such upregulation of BAX and its phosphorylated form (Thr167), dephosphorylation of BAD (Ser 112), and downregulation of MCL-1 and its phosphorylated form (Ser159/Thr 163). Total levels of Bcl-2 were decreased but correlated with increased levels of phosphorylated Bcl-2, which was consistent with our phosphoproteomic analysis predictions. Bcl-2 phosphorylation was regulated by extracellular-signal-regulated kinase (ERK) but not PP2A phosphatase. Although the mechanism linking to Bcl-2 phosphorylation remains to be determined, our findings provide first-hand insights on potential novel combination treatments for AML. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia 2.0)

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15 pages, 3369 KiB

Open AccessArticle

Hydrogel-Based Pre-Clinical Evaluation of Repurposed FDA-Approved Drugs for AML

by Jenna R. James, Johnathan Curd, Jennifer C. Ashworth, Mays Abuhantash, Martin Grundy, Claire H. Seedhouse, Kenton P. Arkill, Amanda J. Wright, Catherine L. R. Merry and Alexander Thompson

Int. J. Mol. Sci. 2023, 24(4), 4235; https://doi.org/10.3390/ijms24044235 - 20 Feb 2023

Cited by 5 | Viewed by 2560

Abstract

In vivo models of acute myeloid leukemia (AML) are low throughput, and standard liquid culture models fail to recapitulate the mechanical and biochemical properties of the extracellular matrix-rich protective bone marrow niche that contributes to drug resistance. Candidate drug discovery in AML requires [...] Read more.

In vivo models of acute myeloid leukemia (AML) are low throughput, and standard liquid culture models fail to recapitulate the mechanical and biochemical properties of the extracellular matrix-rich protective bone marrow niche that contributes to drug resistance. Candidate drug discovery in AML requires advanced synthetic platforms to improve our understanding of the impact of mechanical cues on drug sensitivity in AML. By use of a synthetic, self-assembling peptide hydrogel (SAPH) of modifiable stiffness and composition, a 3D model of the bone marrow niche to screen repurposed FDA-approved drugs has been developed and utilized. AML cell proliferation was dependent on SAPH stiffness, which was optimized to facilitate colony growth. Three candidate FDA-approved drugs were initially screened against the THP-1 cell line and mAF9 primary cells in liquid culture, and EC50 values were used to inform drug sensitivity assays in the peptide hydrogel models. Salinomycin demonstrated efficacy in both an ‘early-stage’ model in which treatment was added shortly after initiation of AML cell encapsulation, and an ‘established’ model in which time-encapsulated cells had started to form colonies. Sensitivity to Vidofludimus treatment was not observed in the hydrogel models, and Atorvastatin demonstrated increased sensitivity in the ‘established’ compared to the ‘early-stage’ model. AML patient samples were equally sensitive to Salinomycin in the 3D hydrogels and partially sensitive to Atorvastatin. Together, this confirms that AML cell sensitivity is drug- and context-specific and that advanced synthetic platforms for higher throughput are valuable tools for pre-clinical evaluation of candidate anti-AML drugs. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia 2.0)

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17 pages, 3173 KiB

Open AccessArticle

by Ying Wang, Yu Liu, Yingxi Xu, Haiyan Xing, Zheng Tian, Kejing Tang, Qing Rao, Min Wang and Jianxiang Wang

Int. J. Mol. Sci. 2023, 24(1), 71; https://doi.org/10.3390/ijms24010071 - 21 Dec 2022

Cited by 2 | Viewed by 1629

Abstract

The AML1-ETO (RUNX1-RUNX1T1) fusion gene created by the chromosome translocation t(8;21) (q21;q22) is one of the essential contributors to leukemogenesis. Only a few studies in the literature have focused on fusion gene-derived circular RNAs (f-circRNAs). Here, we report several AML1-ETO-related fusion [...] Read more.

The AML1-ETO (RUNX1-RUNX1T1) fusion gene created by the chromosome translocation t(8;21) (q21;q22) is one of the essential contributors to leukemogenesis. Only a few studies in the literature have focused on fusion gene-derived circular RNAs (f-circRNAs). Here, we report several AML1-ETO-related fusion circular RNAs (F-CircAEs) in AML1-ETO-positive cell lines and primary patient blasts. Functional studies demonstrate that the over-expression of F-CircAE in NIH3T3 cells promotes cell proliferation in vitro and in vivo. F-CircAE expression enhances the colony formation ability of c-Kit⁺ hematopoietic stem and progenitor cells (HSPCs). Meanwhile, the knockdown of endogenous F-CircAEs can inhibit the proliferation and colony formation ability of AML1-ETO-positive Kasumi-1 cells. Intriguingly, bioinformatic analysis revealed that the glycolysis pathway is down-regulated in F-CircAE-knockdown Kasumi-1 cells and up-regulated in F-CircAE over-expressed NIH3T3 cells. Further studies show that F-CircAE binds to the glycolytic protein ENO-1, up-regulates the expression level of glycolytic enzymes, and enhances lactate production. In summary, our study demonstrates that F-CircAE may exert biological activities on the growth of AML1-ETO leukemia cells by regulating the glycolysis pathway. Determining the role of F-CircAEs in AML1-ETO leukemia can lead to great strides in understanding its pathogenesis, thus providing new diagnostic markers and therapeutic targets. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia 2.0)

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14 pages, 1458 KiB

Open AccessArticle

Evaluation of the Biological Activity of Glucosinolates and Their Enzymolysis Products Obtained from Lepidium meyenii Walp. (Maca)

by Suitong Yan, Jinchao Wei and Rui Chen

Int. J. Mol. Sci. 2022, 23(23), 14756; https://doi.org/10.3390/ijms232314756 - 25 Nov 2022

Cited by 3 | Viewed by 1310

Abstract

Glucosinolates (GLS) were extracted and purified from Lepidium meyenii (Maca) root. Purified GLS were analyzed without desulfation by UPLC–ESI–MS. Glucosinolates were decomposed into benzyl isothiocyanate (BITC) by thioglucosidase. DPPH radical scavenging activity, ABTS radical scavenging activity, and reducing power were used to evaluate [...] Read more.

Glucosinolates (GLS) were extracted and purified from Lepidium meyenii (Maca) root. Purified GLS were analyzed without desulfation by UPLC–ESI–MS. Glucosinolates were decomposed into benzyl isothiocyanate (BITC) by thioglucosidase. DPPH radical scavenging activity, ABTS radical scavenging activity, and reducing power were used to evaluate antioxidant activity of Maca crude extract (MCE), total GLS, and BITC. Maca crude extract showed the highest antioxidant activity among them, and BITC showed no antioxidant activity at concentrations less than 10 mg/mL. Cytotoxicity on five human cancer cell lines and the inhibition rate of NO production were used to evaluate the activity of anti-cancer and anti-inflammatory of total GLS and BITC. The inhibition rate of NO production of 50 μg/mL BITC can reach 99.26% and the cell viability of 100 μg/mL BITC on five tumor cell lines is less than 3%. The results show that BITC may be used as a promising anti-cancer and anti-inflammatory drug. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia 2.0)

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Review

Jump to: Research, Other

21 pages, 36090 KiB

Open AccessReview

A Direct Comparison, and Prioritisation, of the Immunotherapeutic Targets Expressed by Adult and Paediatric Acute Myeloid Leukaemia Cells: A Systematic Review and Meta-Analysis

by Vanessa S. Morris, Hanya Ghazi, Daniel M. Fletcher and Barbara-ann Guinn

Int. J. Mol. Sci. 2023, 24(11), 9667; https://doi.org/10.3390/ijms24119667 - 02 Jun 2023

Viewed by 1857

Abstract

Acute myeloid leukaemia (AML) is characterized by impaired myeloid differentiation resulting in an accumulation of immature blasts in the bone marrow and peripheral blood. Although AML can occur at any age, the incidence peaks at age 65. The pathobiology of AML also varies [...] Read more.

Acute myeloid leukaemia (AML) is characterized by impaired myeloid differentiation resulting in an accumulation of immature blasts in the bone marrow and peripheral blood. Although AML can occur at any age, the incidence peaks at age 65. The pathobiology of AML also varies with age with associated differences in incidence, as well as the frequency of cytogenetic change and somatic mutations. In addition, 5-year survival rates in paediatrics are 60–75% but fall to 5–15% in older AML patients. This systematic review aimed to determine whether the altered genes in AML affect the same molecular pathways, indifferent of patient age, and, therefore, whether patients could benefit from the repurposing drugs or the use of the same immunotherapeutic strategies across age boundaries to prevent relapse. Using a PICO framework and PRISMA-P checklist, relevant publications were identified using five literature databases and assessed against an inclusion criteria, leaving 36 articles, and 71 targets for therapy, for further analysis. QUADAS-2 was used to determine the risk of bias and perform a quality control step. We then priority-ranked the list of cancer antigens based on predefined and pre-weighted objective criteria as part of an analytical hierarchy process used for dealing with complex decisions. This organized the antigens according to their potential to act as targets for the immunotherapy of AML, a treatment that offers an opportunity to remove residual leukaemia cells at first remission and improve survival rates. It was found that 80% of the top 20 antigens identified in paediatric AML were also within the 20 highest scoring immunotherapy targets in adult AML. To analyse the relationships between the targets and their link to different molecular pathways, PANTHER and STRING analyses were performed on the 20 highest scoring immunotherapy targets for both adult and paediatric AML. There were many similarities in the PANTHER and STRING results, including the most prominent pathways being angiogenesis and inflammation mediated by chemokine and cytokine signalling pathways. The coincidence of targets suggests that the repurposing of immunotherapy drugs across age boundaries could benefit AML patients, especially when used in combination with conventional therapies. However, due to cost implications, we would recommend that efforts are focused on ways to target the highest scoring antigens, such as WT1, NRAS, IDH1 and TP53, although in the future other candidates may prove successful. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia 2.0)

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22 pages, 941 KiB

Open AccessReview

CD123 a Therapeutic Target for Acute Myeloid Leukemia and Blastic Plasmocytoid Dendritic Neoplasm

by Elvira Pelosi, Germana Castelli and Ugo Testa

Int. J. Mol. Sci. 2023, 24(3), 2718; https://doi.org/10.3390/ijms24032718 - 01 Feb 2023

Cited by 10 | Viewed by 3418

Abstract

In spite of consistent progress at the level of basic research and of clinical treatment, acute myeloid leukemia (AML) still represents an unmet clinical need for adult and pediatric patients. To improve the outcomes of these patients, it is necessary to identify new [...] Read more.

In spite of consistent progress at the level of basic research and of clinical treatment, acute myeloid leukemia (AML) still represents an unmet clinical need for adult and pediatric patients. To improve the outcomes of these patients, it is necessary to identify new therapeutic targets. IL3RA (CD123, alpha subunit of the interleukin 3 receptor) is a cell membrane protein overexpressed in several hematologic malignancies, including AML blastic plasmocytoid dendritic cell neoplasms (BPDCN). Given the higher expression of CD123 on leukemic cells compared to normal hematopoietic cells and its low/absent expression on normal hematopoietic stem cells, it appears as a suitable and attractive target for therapy. Various drugs targeting CD123 have been developed and evaluated at clinical level: interleukin-3 conjugated with diphtheria toxin; naked neutralizing anti-CD123 antibodies; drug–antibody conjugates; bispecific antibodies targeting both CD123 and CD3; and chimeric antigen receptor (CAR) T cells engineered to target CD123. Some of these agents have shown promising results at the clinical level, including tagraxofusp (CD123 conjugated with diphtheria toxin) for the treatment of BPDCN and IMGN632 (anti-CD123 drug-conjugate), and flotetuzumab (bispecific anti-CD123 and anti-CD3 monoclonal antibody) for the treatment of AML. However, the therapeutic efficacy of CD123-targeting treatments is still unsatisfactory and must be improved through new therapeutic strategies and combined treatments with other antileukemic drugs. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia 2.0)

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Other

Jump to: Research, Review

7 pages, 1043 KiB

Open AccessCase Report

Deep Molecular Response Achieved with Chemotherapy, Dasatinib and Interferon α in Patients with Lymphoid Blast Crisis of Chronic Myeloid Leukaemia

by Lucia Vráblová, Vladimír Divoký, Pavla Kořalková, Kateřina Machová Poláková, Eva Kriegová, Romana Janská, Jan Grohmann, Milena Holzerová, Tomáš Papajík and Edgar Faber

Int. J. Mol. Sci. 2023, 24(3), 2050; https://doi.org/10.3390/ijms24032050 - 20 Jan 2023

Cited by 1 | Viewed by 1545

Abstract

The treatment outcome in patients with chronic myeloid leukaemia (CML) in blast crisis (BC) is unsatisfactory despite the use of allogeneic stem cell transplantation (ASCT). Moreover, in some patients ASCT is contraindicated, with limited treatment options. We report the case series of two [...] Read more.

The treatment outcome in patients with chronic myeloid leukaemia (CML) in blast crisis (BC) is unsatisfactory despite the use of allogeneic stem cell transplantation (ASCT). Moreover, in some patients ASCT is contraindicated, with limited treatment options. We report the case series of two patients with lymphoid BC CML in whom ASCT was not approachable. The first patient developed BC two months after diagnosis in association with dic(7;9)(p11.2;p11.2) and T315I mutation. Blast crisis with central nervous system leukemic involvement and K611N mutation of the SETD2 gene developed abruptly in the second patient five years after ceasing treatment with nilotinib in major molecular response (MMR) at the patient’s request. Both underwent one course of chemotherapy in combination with rituximab and imatinib, followed by dasatinib and interferon α (INFα) treatment in the first and dasatinib alone in the second case. Deep molecular response (DMR; MR 4.0) was achieved within a short time in both cases. It is probable that DMR was caused by a specific immune response to CML cells, described in both agents. The challenging medical condition that prompted these case series, and the subsequent results, suggest a re-visit to the use of a combination of well-known drugs as an area for further investigation. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia 2.0)

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