Cancers

Research

19 pages, 3736 KiB

Open AccessArticle

Anti-Leukemic Effects Induced by Dendritic Cells of Leukemic Origin from Leukemic Blood Samples Are Comparable under Hypoxic vs. Normoxic Conditions

by Fatemeh Doraneh-Gard, Daniel Christoph Amberger, Carina Amend, Melanie Weinmann, Christoph Schwepcke, Lara Klauer, Olga Schutti, Hedayatollah Hosseini, Doris Krämer, Andreas Rank, Christoph Schmid and Helga Maria Schmetzer

Cancers 2024, 16(13), 2383; https://doi.org/10.3390/cancers16132383 - 28 Jun 2024

Cited by 1 | Viewed by 904

Abstract

Hypoxia can modulate the immune system by affecting the function and activity of immune cells, potentially leading to altered immune responses. This study investigated the generation of leukemia-derived dendritic cells (DC_leu) from leukemic blasts and their impact on immune cell activation under [...] Read more.

Hypoxia can modulate the immune system by affecting the function and activity of immune cells, potentially leading to altered immune responses. This study investigated the generation of leukemia-derived dendritic cells (DC_leu) from leukemic blasts and their impact on immune cell activation under hypoxic (5–10% O₂) compared to normoxic (21% O₂) conditions using various immunomodulatory Kits. The results revealed that DC/DC_leu-generation was similar under hypoxic and normoxic conditions, with no significant differences observed in frequencies of generated DC/DC_leu. Furthermore, the study showed that the activation of immune cells and their anti-leukemic activity improved when T cell-enriched immunoreactive cells were co-cultured with DC/DC_leu which were generated with Kit I and M compared to the control after mixed lymphocyte cultures. The anti-leukemic activity was improved under hypoxic compared to normoxic conditions after MLC^{WB-DC Kit M}. These findings suggest that DC/DC_leu-cultures of leukemic whole blood with Kits under hypoxic conditions yield comparable frequencies of DC/DC_leu and can even increase the anti-leukemic activity compared to normoxic conditions. Overall, this research highlights the potential of utilizing DC/DC_leu (potentially induced in vivo with Kits) as a promising approach to enhance immune response in patients with acute myeloid leukemia. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)

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18 pages, 10592 KiB

Open AccessArticle

Identification of a Complex Karyotype Signature with Clinical Implications in AML and MDS-EB Using Gene Expression Profiling

by Cheonghwa Lee, Ha Nui Kim, Jung Ah Kwon, Jinha Hwang, Ji-Ye Park, Ok Sarah Shin, Soo-Young Yoon and Jung Yoon

Cancers 2023, 15(21), 5289; https://doi.org/10.3390/cancers15215289 - 4 Nov 2023

Cited by 1 | Viewed by 1836

Abstract

Complex karyotype (CK) is associated with a poor prognosis in both acute myeloid leukemia (AML) and myelodysplastic syndrome with excess blasts (MDS-EB). Transcriptomic analyses have improved our understanding of the disease and risk stratification of myeloid neoplasms; however, CK-specific gene expression signatures have [...] Read more.

Complex karyotype (CK) is associated with a poor prognosis in both acute myeloid leukemia (AML) and myelodysplastic syndrome with excess blasts (MDS-EB). Transcriptomic analyses have improved our understanding of the disease and risk stratification of myeloid neoplasms; however, CK-specific gene expression signatures have been rarely investigated. In this study, we developed and validated a CK-specific gene expression signature. Differential gene expression analysis between the CK and non-CK groups using data from 348 patients with AML and MDS-EB from four cohorts revealed enrichment of the downregulated genes localized on chromosome 5q or 7q, suggesting that haploinsufficiency due to the deletion of these chromosomes possibly underlies CK pathogenesis. We built a robust transcriptional model for CK prediction using LASSO regression for gene subset selection and validated it using the leave-one-out cross-validation method for fitting the logistic regression model. We established a 10-gene CK signature (CKS) predictive of CK with high predictive accuracy (accuracy 94.22%; AUC 0.977). CKS was significantly associated with shorter overall survival in three independent cohorts, and was comparable to that of previously established risk stratification models for AML. Furthermore, we explored of therapeutic targets among the genes comprising CKS and identified the dysregulated expression of superoxide dismutase 1 (SOD1) gene, which is potentially amenable to SOD1 inhibitors. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)

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21 pages, 3446 KiB

Open AccessArticle

Acute Myeloid Leukemia Expresses a Specific Group of Olfactory Receptors

by Gabriela D. A. Guardia, Rafaella G. Naressi, Vanessa C. Buzzato, Juliana B. da Costa, Ilana Zalcberg, Jordana Ramires, Bettina Malnic, Luciana M. Gutiyama and Pedro A. F. Galante

Cancers 2023, 15(12), 3073; https://doi.org/10.3390/cancers15123073 - 6 Jun 2023

Cited by 2 | Viewed by 2071

Abstract

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, with a 5-year overall survival rate of approximately 30%. Despite recent advances in therapeutic options, relapse remains the leading cause of death and poor survival outcomes. New drugs benefit [...] Read more.

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, with a 5-year overall survival rate of approximately 30%. Despite recent advances in therapeutic options, relapse remains the leading cause of death and poor survival outcomes. New drugs benefit specific small subgroups of patients with actionable therapeutic targets. Thus, finding new targets with greater applicability should be pursued. Olfactory receptors (ORs) are seven transmembrane G-protein coupled receptors preferentially expressed in sensory neurons with a critical role in recognizing odorant molecules. Recent studies have revealed ectopic expression and putative function of ORs in nonolfactory tissues and pathologies, including AML. Here, we investigated OR expression in 151 AML samples, 6400 samples of 15 other cancer types, and 11,200 samples of 51 types of healthy tissues. First, we identified 19 ORs with a distinct and major expression pattern in AML, which were experimentally validated by RT-PCR in an independent set of 13 AML samples, 13 healthy donors, and 8 leukemia cell lines. We also identified an OR signature with prognostic potential for AML patients. Finally, we found cancer-related genes coexpressed with the ORs in the AML samples. In summary, we conducted an extensive study to identify ORs that can be used as novel biomarkers for the diagnosis of AML and as potential drug targets. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)

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19 pages, 3631 KiB

Open AccessArticle

Transgenic HA-1-Specific CD8⁺ T-Lymphocytes Selectively Target Leukemic Cells

by Artem Pilunov, Dmitrii S. Romaniuk, Anton Shmelev, Savely Sheetikov, Anna N. Gabashvili, Alexandra Khmelevskaya, Dmitry Dianov, Ksenia Zornikova, Naina T. Shakirova, Murad Vagida, Apollinariya Bogolyubova and Grigory A. Efimov

Cancers 2023, 15(5), 1592; https://doi.org/10.3390/cancers15051592 - 3 Mar 2023

Cited by 3 | Viewed by 2450

Abstract

A significant share of allogeneic hematopoietic stem cell transplantations (allo-HSCT) results in the relapse of malignant disease. The T cell immune response to minor histocompatibility antigens (MiHAs) promotes a favorable graft-versus-leukemia response. The immunogenic MiHA HA-1 is a promising target for leukemia immunotherapy, [...] Read more.

A significant share of allogeneic hematopoietic stem cell transplantations (allo-HSCT) results in the relapse of malignant disease. The T cell immune response to minor histocompatibility antigens (MiHAs) promotes a favorable graft-versus-leukemia response. The immunogenic MiHA HA-1 is a promising target for leukemia immunotherapy, as it is predominantly expressed in hematopoietic tissues and presented by the common HLA A*02:01 allele. Adoptive transfer of HA-1-specific modified CD8⁺ T cells could complement allo-HSCT from HA-1- donors to HA-1+ recipients. Using bioinformatic analysis and a reporter T cell line, we discovered 13 T cell receptors (TCRs) specific for HA-1. Their affinities were measured by the response of the TCR-transduced reporter cell lines to HA-1+ cells. The studied TCRs showed no cross-reactivity to the panel of donor peripheral mononuclear blood cells with 28 common HLA alleles. CD8⁺ T cells after endogenous TCR knock out and introduction of transgenic HA-1-specific TCR were able to lyse hematopoietic cells from HA-1+ patients with acute myeloid, T-, and B-cell lymphocytic leukemia (n = 15). No cytotoxic effect was observed on cells from HA-1- or HLA-A*02-negative donors (n = 10). The results support the use of HA-1 as a target for post-transplant T cell therapy. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)

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14 pages, 2879 KiB

Open AccessArticle

TP-0903 Is Active in Preclinical Models of Acute Myeloid Leukemia with TP53 Mutation/Deletion

by Eric D. Eisenmann, Jack C. Stromatt, Sydney Fobare, Kevin M. Huang, Daelynn R. Buelow, Shelley Orwick, Jae Yoon Jeon, Robert H. Weber, Bill Larsen, Alice S. Mims, Erin Hertlein, John C. Byrd and Sharyn D. Baker

Cancers 2023, 15(1), 29; https://doi.org/10.3390/cancers15010029 - 21 Dec 2022

Cited by 4 | Viewed by 2668

Abstract

Acute myeloid leukemia (AML) with mutations in the tumor suppressor gene TP53 confers a dismal prognosis with 3-year overall survival of <5%. While inhibition of kinases involved in cell cycle regulation induces synthetic lethality in a variety of TP53 mutant cancers, this strategy [...] Read more.

Acute myeloid leukemia (AML) with mutations in the tumor suppressor gene TP53 confers a dismal prognosis with 3-year overall survival of <5%. While inhibition of kinases involved in cell cycle regulation induces synthetic lethality in a variety of TP53 mutant cancers, this strategy has not been evaluated in mutant TP53 AML. Previously, we demonstrated that TP-0903 is a novel multikinase inhibitor with low nM activity against AURKA/B, Chk1/2, and other cell cycle regulators. Here, we evaluated the preclinical activity of TP-0903 in TP53 mutant AML cell lines, including a single-cell clone of MV4-11 containing a TP53 mutation (R248W), Kasumi-1 (R248Q), and HL-60 (TP 53 null). TP-0903 inhibited cell viability (IC50, 12–32 nM) and induced apoptosis at 50 nM. By immunoblot, 50 nM TP-0903 upregulated pChk1/2 and pH2AX, suggesting induction of DNA damage. The combination of TP-0903 and decitabine was additive in vitro, and in vivo significantly prolonged median survival compared to single-agent treatments in mice xenografted with HL-60 (vehicle, 46 days; decitabine, 55 days; TP-0903, 63 days; combination, 75 days) or MV4-11 (R248W) (51 days; 62 days; 81 days; 89 days) (p < 0.001). Together, these results provide scientific premise for the clinical evaluation of TP-0903 in combination with decitabine in TP53 mutant AML. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)

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Review

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16 pages, 727 KiB

Open AccessReview

Treatment of Acute Myeloid Leukemia in Older Adults

by Aseel Alsouqi, Emily Geramita and Annie Im

Cancers 2023, 15(22), 5409; https://doi.org/10.3390/cancers15225409 - 14 Nov 2023

Cited by 3 | Viewed by 3890

Abstract

Acute Myeloid Leukemia (AML) is an aggressive myeloid malignancy predominantly affecting older adults. Despite the advancements in new therapies for AML, older and medically unfit patients continue to suffer from poor outcomes due to disease-related factors such as the mutational profile and patient-related [...] Read more.

Acute Myeloid Leukemia (AML) is an aggressive myeloid malignancy predominantly affecting older adults. Despite the advancements in new therapies for AML, older and medically unfit patients continue to suffer from poor outcomes due to disease-related factors such as the mutational profile and patient-related factors such as comorbidities and performance status. In this review, we discuss a spectrum of therapeutic options for older patients with AML starting with a historical perspective and ending with therapies being investigated in clinical trials. We review the standard of care treatment options including combination venetoclax and hypomethylating agents, in addition to targeted therapies such as FLT3 and IDH inhibitors. Lastly, we shed light on challenges facing the care of older adults and their representation in clinical trials. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)

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16 pages, 1255 KiB

Open AccessReview

TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited

by Dong-Yeop Shin

Cancers 2023, 15(19), 4816; https://doi.org/10.3390/cancers15194816 - 30 Sep 2023

Cited by 9 | Viewed by 3738

Abstract

Introduction: TP53 is the most commonly mutated gene in human cancers and was the first tumor suppressor gene to be discovered in the history of medical science. Mutations in the TP53 gene occur at various genetic locations and exhibit significant heterogeneity among patients. [...] Read more.

Introduction: TP53 is the most commonly mutated gene in human cancers and was the first tumor suppressor gene to be discovered in the history of medical science. Mutations in the TP53 gene occur at various genetic locations and exhibit significant heterogeneity among patients. Mutations occurring primarily within the DNA-binding domain of TP53 result in the loss of the p53 protein’s DNA-binding capability. However, a complex phenotypic landscape often combines gain-of-function, dominant negative, or altered specificity features. This complexity poses a significant challenge in developing an effective treatment strategy, which eradicates TP53-mutated cancer clones. This review summarizes the current understanding of TP53 mutations in AML and their implications. TP53 mutation in AML: In patients with acute myeloid leukemia (AML), six hotspot mutations (R175H, G245S, R248Q/W, R249S, R273H/S, and R282W) within the DNA-binding domain are common. TP53 mutations are frequently associated with a complex karyotype and subgroups of therapy-related or secondary AML. The presence of TP53 mutation is considered as a poor prognostic factor. TP53-mutated AML is even classified as a distinct subgroup of AML by itself, as TP53-mutated AML exhibits a significantly distinct landscape in terms of co-mutation and gene expression profiles compared with wildtype (WT)-TP53 AML. Clinical Implications: To better predict the prognosis in cancer patients with different TP53 mutations, several predictive scoring systems have been proposed based on screening experiments, to assess the aggressiveness of TP53-mutated cancer cells. Among those scoring systems, a relative fitness score (RFS) could be applied to AML patients with TP53 mutations in terms of overall survival (OS) and event-free survival (EFS). The current standard treatment, which includes cytotoxic chemotherapy and allogeneic hematopoietic stem cell transplantation, is largely ineffective for patients with TP53-mutated AML. Consequently, most patients with TP53-mutated AML succumb to leukemia within several months, despite active anticancer treatment. Decitabine, a hypomethylating agent, is known to be relatively effective in patients with AML. Numerous trials are ongoing to investigate the effects of novel drugs combined with hypomethylating agents, TP53-targeting agents or immunologic agents. Conclusions: Developing an effective treatment strategy for TP53-mutated AML through innovative and multidisciplinary research is an urgent task. Directly targeting mutated TP53 holds promise as an approach to combating TP53-mutated AML, and recent developments in immunologic agents for AML offer hope in this field. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)

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15 pages, 2285 KiB

Open AccessReview

Building on Foundations: Venetoclax-Based Combinations in the Treatment of Acute Myeloid Leukemia

by Emmanuella Oyogoa, Elie Traer, Jeffrey Tyner and Curtis Lachowiez

Cancers 2023, 15(14), 3589; https://doi.org/10.3390/cancers15143589 - 12 Jul 2023

Cited by 8 | Viewed by 3817

Abstract

Frontline acute myeloid leukemia (AML) treatment is determined by a combination of patient and genetic factors. This includes patient fitness (i.e., comorbidities that increase the risk of treatment-related mortality) and genetic characteristics, including cytogenetic events and gene mutations. In older unfit patients, the [...] Read more.

Frontline acute myeloid leukemia (AML) treatment is determined by a combination of patient and genetic factors. This includes patient fitness (i.e., comorbidities that increase the risk of treatment-related mortality) and genetic characteristics, including cytogenetic events and gene mutations. In older unfit patients, the standard of care treatment is typically venetoclax (VEN) combined with hypomethylating agents (HMA). Recently, several drugs have been developed targeting specific genomic subgroups of AML patients, enabling individualized therapy. This has resulted in investigations of doublet and triplet combinations incorporating VEN aimed at overcoming known resistance mechanisms and improving outcomes in older patients with AML. These combinations include isocitrate dehydrogenase-1/2 (IDH1/2) inhibitors (i.e., ivosidenib and enasidenib), fms-like tyrosine kinase 3 (FLT3) inhibitors (i.e., gilteritinib), anti-CD47 antibodies (i.e., magrolimab), mouse double minute-2 (MDM2) inhibitors, and p53 reactivators (i.e., eprenetapopt). This review summarizes ongoing trials aimed at overcoming known VEN resistance mechanisms and improving outcomes beyond that observed with HMA + VEN combinations in the treatment of AML. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)

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27 pages, 846 KiB

Open AccessReview

Modern Risk Stratification of Acute Myeloid Leukemia in 2023: Integrating Established and Emerging Prognostic Factors

by Eleonora Boscaro, Irene Urbino, Federica Maria Catania, Giulia Arrigo, Carolina Secreto, Matteo Olivi, Stefano D’Ardia, Chiara Frairia, Valentina Giai, Roberto Freilone, Dario Ferrero, Ernesta Audisio and Marco Cerrano

Cancers 2023, 15(13), 3512; https://doi.org/10.3390/cancers15133512 - 6 Jul 2023

Cited by 8 | Viewed by 6856

Abstract

An accurate estimation of AML prognosis is complex since it depends on patient-related factors, AML manifestations at diagnosis, and disease genetics. Furthermore, the depth of response, evaluated using the level of MRD, has been established as a strong prognostic factor in several AML [...] Read more.

An accurate estimation of AML prognosis is complex since it depends on patient-related factors, AML manifestations at diagnosis, and disease genetics. Furthermore, the depth of response, evaluated using the level of MRD, has been established as a strong prognostic factor in several AML subgroups. In recent years, this rapidly evolving field has made the prognostic evaluation of AML more challenging. Traditional prognostic factors, established in cohorts of patients treated with standard intensive chemotherapy, are becoming less accurate as new effective therapies are emerging. The widespread availability of next-generation sequencing platforms has improved our knowledge of AML biology and, consequently, the recent ELN 2022 recommendations significantly expanded the role of new gene mutations. However, the impact of rare co-mutational patterns remains to be fully disclosed, and large international consortia such as the HARMONY project will hopefully be instrumental to this aim. Moreover, accumulating evidence suggests that clonal architecture plays a significant prognostic role. The integration of clinical, cytogenetic, and molecular factors is essential, but hierarchical methods are reaching their limit. Thus, innovative approaches are being extensively explored, including those based on “knowledge banks”. Indeed, more robust prognostic estimations can be obtained by matching each patient’s genomic and clinical data with the ones derived from very large cohorts, but further improvements are needed. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)

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18 pages, 1320 KiB

Open AccessReview

Acute Myeloid Leukemia Stem Cells in Minimal/Measurable Residual Disease Detection

by Kritika Srinivasan Rajsri, Nainita Roy and Sohini Chakraborty

Cancers 2023, 15(10), 2866; https://doi.org/10.3390/cancers15102866 - 22 May 2023

Cited by 4 | Viewed by 2351 | Correction

Abstract

Acute myeloid leukemia (AML) is a hematological malignancy characterized by an abundance of incompletely matured or immature clonally derived hematopoietic precursors called leukemic blasts. Rare leukemia stem cells (LSCs) that can self-renew as well as give rise to leukemic progenitors comprising the bulk [...] Read more.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by an abundance of incompletely matured or immature clonally derived hematopoietic precursors called leukemic blasts. Rare leukemia stem cells (LSCs) that can self-renew as well as give rise to leukemic progenitors comprising the bulk of leukemic blasts are considered the cellular reservoir of disease initiation and maintenance. LSCs are widely thought to be relatively resistant as well as adaptive to chemotherapy and can cause disease relapse. Therefore, it is imperative to understand the molecular bases of LSC forms and functions during different stages of disease progression, so we can more accurately identify these cells and design therapies to target them. Irrespective of the morphological, cytogenetic, and cellular heterogeneity of AML, the uniform, singularly important and independently significant prognosticator of disease response to therapy and patient outcome is measurable or minimal residual disease (MRD) detection, defined by residual disease detection below the morphology-based 5% blast threshold. The importance of LSC identification and frequency estimation during MRD detection, in order to make MRD more effective in predicting disease relapse and modifying therapeutic regimen is becoming increasingly apparent. This review focuses on summarizing functional and cellular composition-based LSC identification and linking those studies to current techniques of MRD detection to suggest LSC-inclusive MRD detection as well as outline outstanding questions that need to be addressed to improve the future of AML clinical management and treatment outcomes. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)

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13 pages, 1138 KiB

Open AccessReview

Optical Genome Mapping for Cytogenetic Diagnostics in AML

by Verena Nilius-Eliliwi, Wanda M. Gerding, Roland Schroers, Huu Phuc Nguyen and Deepak B. Vangala

Cancers 2023, 15(6), 1684; https://doi.org/10.3390/cancers15061684 - 9 Mar 2023

Cited by 19 | Viewed by 4291

Abstract

The classification and risk stratification of acute myeloid leukemia (AML) is based on reliable genetic diagnostics. A broad and expanding variety of relevant aberrations are structural variants beyond single-nucleotide variants. Optical Genome Mapping is an unbiased, genome-wide, amplification-free method for the detection of [...] Read more.

The classification and risk stratification of acute myeloid leukemia (AML) is based on reliable genetic diagnostics. A broad and expanding variety of relevant aberrations are structural variants beyond single-nucleotide variants. Optical Genome Mapping is an unbiased, genome-wide, amplification-free method for the detection of structural variants. In this review, the current knowledge of Optical Genome Mapping (OGM) with regard to diagnostics in hematological malignancies in general, and AML in specific, is summarized. Furthermore, this review focuses on the ability of OGM to expand the use of cytogenetic diagnostics in AML and perhaps even replace older techniques such as chromosomal-banding analysis, fluorescence in situ hybridization, or copy number variation microarrays. Finally, OGM is compared to amplification-based techniques and a brief outlook for future directions is given. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)

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21 pages, 1222 KiB

Open AccessReview

Molecularly Targeted Therapy in Acute Myeloid Leukemia: Current Treatment Landscape and Mechanisms of Response and Resistance

by Curtis A. Lachowiez, Courtney D. DiNardo and Sanam Loghavi

Cancers 2023, 15(5), 1617; https://doi.org/10.3390/cancers15051617 - 6 Mar 2023

Cited by 6 | Viewed by 5638

Abstract

Treatment for acute myeloid leukemia (AML) has evolved rapidly over the last decade as improved understanding of cytogenetic and molecular drivers of leukemogenesis refined survival prognostication and enabled development of targeted therapeutics. Molecularly targeted therapies are now approved for the treatment of FLT3 [...] Read more.

Treatment for acute myeloid leukemia (AML) has evolved rapidly over the last decade as improved understanding of cytogenetic and molecular drivers of leukemogenesis refined survival prognostication and enabled development of targeted therapeutics. Molecularly targeted therapies are now approved for the treatment of FLT3 and IDH1/2-mutated AML and additional molecularly and cellularly targeted therapeutics are in development for defined patient subgroups. Alongside these welcome therapeutic advancements, increased understanding of leukemic biology and treatment resistance has resulted in clinical trials investigating combinations of cytotoxic, cellular, and molecularly targeted therapeutics resulting in improved response and survival outcomes in patients with AML. Herein, we comprehensively review the current landscape of IDH and FLT3 inhibitors in clinical practice for the treatment of AML, highlight known resistance mechanisms, and discuss new cellular or molecularly targeted therapies currently under investigation in ongoing early phase clinical trials. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)

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