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16 pages, 2494 KiB

Open AccessArticle

Magrolimab Therapy in Conjunction with Conventional Chemotherapeutics Slows Disease Progression in Pediatric Acute Myeloid Leukemia Patient-Derived Xenograft Models

by Julia G. Kim, Sohani K. Sandhu, Ritesh V. Dontula, Josh J. Cooper, Jaden Sherman, Max Rochette, Rehan Siddiqui, Lana E. Kim, Michelle S. Redell and Alexandra M. Stevens

Cancers 2025, 17(9), 1509; https://doi.org/10.3390/cancers17091509 (registering DOI) - 29 Apr 2025

Abstract

Background/Objectives: Magrolimab (Magro) is a humanized naked anti-CD47 monoclonal antibody that blocks the SIRPα CD47 interaction, allowing macrophages to target and destroy cancer cells. To evaluate its preclinical efficacy in vivo, Magro was tested as a single agent and in combination with conventional [...] Read more.

Background/Objectives: Magrolimab (Magro) is a humanized naked anti-CD47 monoclonal antibody that blocks the SIRPα CD47 interaction, allowing macrophages to target and destroy cancer cells. To evaluate its preclinical efficacy in vivo, Magro was tested as a single agent and in combination with conventional chemotherapy drugs, Cytarabine (Ara-C) or Azacitidine (Aza), in three pediatric AML (pAML) patient-derived xenograft (PDX) models—AML006 (KMT2A::MLLT1), AML010 (+10, WT1), and AML013 (KMT2A::MLLT4). Methods: After PDX model establishment, mice were assigned to treatment groups hulgG4 (VC, vehicle control for Magro), Magro, Ara-C + VC, Aza + VC, Ara-C + Magro, and Aza + Magro, and then followed for survival. Mice that met humane euthanasia endpoints and at the culmination of experimental timelines had tissues harvested to measure disease burden. Results: Magro alone significantly improved survival in AML006 (p < 0.0001) and AML013 (p = 0.003) and decreased bone marrow (BM) disease burden in AML006 (p = 0.009) and AML013 (p = 0.002). Ara-C + Magro therapy led to significantly improved survival in all three models and significantly decreased BM disease burden in AML006 (p < 0.0001) and AML013 (p = 0.048). Aza + Magro therapy led to significantly improved survival in AML013 (p = 0.047) and AML010 (p = 0.017) and significantly lower BM disease burden in AML010 (p = 0.001). Conclusions: Interestingly, the two models that demonstrated improvement in survival with Magro harbored KMT2A rearrangements, suggesting a subset of patients that may be more responsive to the effects of CD47 blockade. As this drug is being evaluated for use in other malignancies, future studies may focus on investigating the importance of biomarker-based patient selection. Full article

(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)

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12 pages, 1060 KiB

Open AccessArticle

Preclinical Assessment of Dactinomycin in KMT2A-Rearranged Infant Acute Lymphoblastic Leukemia

by Sung K. Chiu, Emanuela Ferrari, Joyce Oommen, Sebastien Malinge, Laurence C. Cheung and Rishi S. Kotecha

Cancers 2025, 17(3), 527; https://doi.org/10.3390/cancers17030527 - 5 Feb 2025

Viewed by 684

Abstract

Background/Objectives: Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have high rates of relapse and poor survival compared with children. Few new therapies have been identified over the past twenty years. The aim of this study was to identify existing anti-cancer [...] Read more.

Background/Objectives: Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have high rates of relapse and poor survival compared with children. Few new therapies have been identified over the past twenty years. The aim of this study was to identify existing anti-cancer agents that have the potential to be repurposed for the treatment of infant ALL. Methods: Eight extensively characterized infant ALL cell lines were treated with 62 anti-neoplastic drugs in vitro to identify agents that exhibit significant cytotoxicity. From this screen, we selected the most effective and clinically translatable agent for further in vitro and in vivo assessment to determine the potential for use in the clinical setting. Results: Our anti-cancer drug screen revealed significant activity of dactinomycin across all infant ALL cell lines. Further in vitro testing identified low half-maximal inhibitory concentrations (IC₅₀) across our infant ALL cell lines in the nanomolar range. Combination testing with the conventional chemotherapeutic agents currently used to treat infants with ALL demonstrated additivity with cytarabine. In vivo assessment of dactinomycin identified 36 μg/kg as the maximum tolerated dose, with unacceptable toxicities at higher dose treatment. Treatment using doses of 18 μg/kg administered either once or twice a week derived a small but significant survival benefit in patient-derived xenografts. Conclusions: Dactinomycin is extensively used for the treatment of solid tumors in children and has an acceptable safety profile when used to treat infants in this context. However, despite being readily translational and exhibiting promising in vitro cytotoxicity, dactinomycin showed limited efficacy in vivo and therefore does not represent a priority candidate for integrating into therapy for infants with ALL. Full article

(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)

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14 pages, 1699 KiB

Open AccessArticle

Expression and Prognostic Value of a Novel B7-H3 (CD276) Antibody in Acute Myeloid Leukemia

by Sylwia A. Stefańczyk, Clara Hayn, Jonas Heitmann, Susanne Jung, Latifa Zekri and Melanie Märklin

Cancers 2024, 16(13), 2455; https://doi.org/10.3390/cancers16132455 - 4 Jul 2024

Cited by 1 | Viewed by 2065

Abstract

Despite recent advances in immunophenotyping, the prognosis of acute myeloid leukemia (AML) is still mainly estimated using age and genetic markers. As the genetic heterogeneity of AML patients is high, flow cytometry-based classification with appropriate biomarkers can efficiently complement risk stratification and treatment [...] Read more.

Despite recent advances in immunophenotyping, the prognosis of acute myeloid leukemia (AML) is still mainly estimated using age and genetic markers. As the genetic heterogeneity of AML patients is high, flow cytometry-based classification with appropriate biomarkers can efficiently complement risk stratification and treatment selection. An increased expression of B7-H3 (CD276), an immune checkpoint protein, has been reported and associated with poor prognosis. However, the available data are limited and heterogeneous. Here, we used a novel, proprietary murine anti-B7-H3 8H8 antibody for the flow cytometric analysis of B7-H3 expression in AML blasts from 77 patients. Our antibody reliably detected substantial B7-H3 expression in 62.3% of AML patients. B7-H3 expression was higher in the monocytic French–American–British (FAB) M5 group and in intermediate and poor risk patients according to the European Leukemia Network. Using receiver operating characteristics (ROCs), we identified a specific fluorescence intensity cut-off of 4.45 to discriminate between B7-H3^high and B7-H3^low expression. High B7-H3 expression was associated with shorter overall survival (OS) and progression-free survival (PFS). In conclusion, we have developed a novel B7-H3 antibody that serves as a new tool for the detection of B7-H3 expression in AML and may help to facilitate risk stratification and treatment selection in AML patients. Full article

(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)

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23 pages, 3657 KiB

Open AccessArticle

PARP1 Characterization as a Potential Biomarker for BCR::ABL1 p190+ Acute Lymphoblastic Leukemia

by Caio Bezerra Machado, Emerson Lucena da Silva, Wallax Augusto Silva Ferreira, Flávia Melo Cunha de Pinho Pessoa, Andreza Urba de Quadros, Daianne Maciely Carvalho Fantacini, Izadora Peter Furtado, Rafaela Rossetti, Roberta Maraninchi Silveira, Sarah Caroline Gomes de Lima, Fernando Augusto Rodrigues Mello Júnior, Aline Damasceno Seabra, Edith Cibelle de Oliveira Moreira, Manoel Odorico de Moraes Filho, Maria Elisabete Amaral de Moraes, Raquel Carvalho Montenegro, Rodrigo Monteiro Ribeiro, André Salim Khayat, Rommel Mário Rodriguez Burbano, Edivaldo Herculano Correa de Oliveira, Dimas Tadeu Covas, Lucas Eduardo Botelho de Souza and Caroline de Fátima Aquino Moreira-Nunes Show full author list Hide full author list

Cancers 2023, 15(23), 5510; https://doi.org/10.3390/cancers15235510 - 22 Nov 2023

Cited by 1 | Viewed by 1647

Abstract

Detection of t(9;22), and consequent BCR::ABL1 fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated [...] Read more.

Detection of t(9;22), and consequent BCR::ABL1 fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated the effectiveness of targeting poly-ADP-ribose polymerase (PARP) in a model of BCR::ABL1 p190+ ALL, the most common isoform to afflict ALL patients, and demonstrated the use of experimental PARP inhibitor (PARPi), AZD2461, as a therapeutic option with cytotoxic capabilities similar to that of imatinib, the current gold standard in medical care. We characterized cytostatic profiles, induced cell death, and biomarker expression modulation utilizing cell models, also providing a comprehensive genome-wide analysis through an aCGH of the model used, and further validated PARP1 differential expression in samples of ALL p190+ patients from local healthcare institutions, as well as in larger cohorts of online and readily available datasets. Overall, we demonstrate the effectiveness of PARPi in the treatment of BCR::ABL1 p190+ ALL cell models and that PARP1 is differentially expressed in patient samples. We hope our findings help expand the characterization of molecular profiles in ALL settings and guide future investigations into novel biomarker detection and pharmacological choices in clinical practice. Full article

(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)

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16 pages, 3315 KiB

Open AccessArticle

Epigenetic Profiling of PTPN11 Mutant JMML Hematopoietic Stem and Progenitor Cells Reveals an Aberrant Histone Landscape

by Roshani Sinha, Mai Dvorak, Ananthakrishnan Ganesan, Larry Kalesinskas, Charlotte M. Niemeyer, Christian Flotho, Kathleen M. Sakamoto, Norman Lacayo, Rachana Vinay Patil, Rhonda Perriman, Alma-Martina Cepika, Yunying Lucy Liu, Alex Kuo, Paul J. Utz, Purvesh Khatri and Alice Bertaina

Cancers 2023, 15(21), 5204; https://doi.org/10.3390/cancers15215204 - 29 Oct 2023

Viewed by 2271

Abstract

Juvenile myelomonocytic leukemia (JMML) is a deadly pediatric leukemia driven by RAS pathway mutations, of which >35% are gain-of-function in PTPN11. Although DNA hypermethylation portends severe clinical phenotypes, the landscape of histone modifications and chromatin profiles in JMML patient cells have not [...] Read more.

Juvenile myelomonocytic leukemia (JMML) is a deadly pediatric leukemia driven by RAS pathway mutations, of which >35% are gain-of-function in PTPN11. Although DNA hypermethylation portends severe clinical phenotypes, the landscape of histone modifications and chromatin profiles in JMML patient cells have not been explored. Using global mass cytometry, Epigenetic Time of Flight (EpiTOF), we analyzed hematopoietic stem and progenitor cells (HSPCs) from five JMML patients with PTPN11 mutations. These data revealed statistically significant changes in histone methylation, phosphorylation, and acetylation marks that were unique to JMML HSPCs when compared with healthy controls. Consistent with these data, assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis revealed significant alterations in chromatin profiles at loci encoding post-translational modification enzymes, strongly suggesting their mis-regulated expression. Collectively, this study reveals histone modification pathways as an additional epigenetic abnormality in JMML patient HSPCs, thereby uncovering a new family of potential druggable targets for the treatment of JMML. Full article

(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)

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16 pages, 2866 KiB

Open AccessArticle

MicroRNA Expression Patterns Reveal a Role of the TGF-β Family Signaling in AML Chemo-Resistance

by Paula Reichelt, Stephan Bernhart, Franziska Wilke, Sebastian Schwind, Michael Cross, Uwe Platzbecker and Gerhard Behre

Cancers 2023, 15(20), 5086; https://doi.org/10.3390/cancers15205086 - 21 Oct 2023

Cited by 3 | Viewed by 1893

Abstract

Resistance to chemotherapy is ultimately responsible for the majority of AML-related deaths, making the identification of resistance pathways a high priority. Transcriptomics approaches can be used to identify genes regulated at the level of transcription or mRNA stability but miss microRNA-mediated changes in [...] Read more.

Resistance to chemotherapy is ultimately responsible for the majority of AML-related deaths, making the identification of resistance pathways a high priority. Transcriptomics approaches can be used to identify genes regulated at the level of transcription or mRNA stability but miss microRNA-mediated changes in translation, which are known to play a role in chemo-resistance. To address this, we compared miRNA profiles in paired chemo-sensitive and chemo-resistant subclones of HL60 cells and used a bioinformatics approach to predict affected pathways. From a total of 38 KEGG pathways implicated, TGF-β/activin family signaling was selected for further study. Chemo-resistant HL60 cells showed an increased TGF-β response but were not rendered chemo-sensitive by specific inhibitors. Differential pathway expression in primary AML samples was then investigated at the RNA level using publically available gene expression data in the TGCA database and by longitudinal analysis of pre- and post-resistance samples available from a limited number of patients. This confirmed differential expression and activity of the TGF-β family signaling pathway upon relapse and revealed that the expression of TGF-β and activin signaling genes at diagnosis was associated with overall survival. Our focus on a matched pair of cytarabine sensitive and resistant sublines to identify miRNAs that are associated specifically with resistance, coupled with the use of pathway analysis to rank predicted targets, has thus identified the activin/TGF-β signaling cascade as a potential target for overcoming resistance in AML. Full article

(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)

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Review

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13 pages, 267 KiB

Open AccessReview

New Approaches for the Treatment of AML beyond the 7+3 Regimen: Current Concepts and New Approaches

by Jaime L. Roman Diaz, Mariola Vazquez Martinez and Farhad Khimani

Cancers 2024, 16(3), 677; https://doi.org/10.3390/cancers16030677 - 5 Feb 2024

Cited by 11 | Viewed by 3747

Abstract

Fifty years have passed since the development of the first chemotherapy regimen for treating acute myelogenous leukemia (AML), with the approval in 1973 of the cytarabine daunorubicin (7+3) regimen. Until recently, patients diagnosed with AML had very limited treatment options and depended primarily [...] Read more.

Fifty years have passed since the development of the first chemotherapy regimen for treating acute myelogenous leukemia (AML), with the approval in 1973 of the cytarabine daunorubicin (7+3) regimen. Until recently, patients diagnosed with AML had very limited treatment options and depended primarily on chemotherapy in combinations, doses, or schedules of the same drugs. Patients with advanced age, comorbidities, or relapsed or refractory disease were left with no effective options for treatment. New advances in the understanding of the biology and the molecular and genetic changes associated with leukemogenesis, as well as recent advances in drug development, have resulted in the introduction over the last few years of novel therapeutic agents and approaches to the treatment of AML as well as a new classification of the disease. In this article, we will discuss the new classification of AML; the mechanisms, actions, and indications of the new targeted therapies; the chemotherapy combinations; and the potential role of cellular therapies as new treatment options for this terrible disease. Full article

(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)

11 pages, 482 KiB

Open AccessReview

Impact of Next-Generation Sequencing in Diagnosis, Prognosis and Therapeutic Management of Acute Myeloid Leukemia/Myelodysplastic Neoplasms

by Lamia Madaci, Laure Farnault, Norman Abbou, Jean Gabert, Geoffroy Venton and Régis Costello

Cancers 2023, 15(13), 3280; https://doi.org/10.3390/cancers15133280 - 22 Jun 2023

Cited by 4 | Viewed by 2141

Abstract

For decades, the diagnosis, prognosis and thus, the treatment of acute myeloblastic leukemias and myelodysplastic neoplasms has been mainly based on morphological aspects, as evidenced by the French-American-British classification. The morphological aspects correspond quite well, in a certain number of particular cases, to [...] Read more.

For decades, the diagnosis, prognosis and thus, the treatment of acute myeloblastic leukemias and myelodysplastic neoplasms has been mainly based on morphological aspects, as evidenced by the French-American-British classification. The morphological aspects correspond quite well, in a certain number of particular cases, to particular evolutionary properties, such as acute myelomonoblastic leukemias with eosinophils or acute promyelocytic leukemias. Advances in biology, particularly “classical” cytogenetics (karyotype) and molecular cytogenetics (in situ hybridization), have made it possible to associate certain morphological features with particular molecular abnormalities, such as the pericentric inversion of chromosome 16 and translocation t(15;17) in the two preceding examples. Polymerase chain reaction techniques have made it possible to go further in these analyses by associating these karyotype abnormalities with their molecular causes, CBFbeta fusion with MYH11 and PML-RAR fusion in the previous cases. In these two examples, the molecular abnormality allows us to better define the pathophysiology of leukemia, to adapt certain treatments (all-transretinoic acid, for example), and to follow up the residual disease of strong prognostic value beyond the simple threshold of less than 5% of marrow blasts, signaling the complete remission. However, the new sequencing techniques of the next generation open up broader perspectives by being able to analyze several dozens of molecular abnormalities, improving all levels of management, from diagnosis to prognosis and treatment, even if it means that morphological aspects are increasingly relegated to the background. Full article

(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)

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