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Cancers
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Stem Cells in Leukemia: From Biological Properties to Therapeutic Targeting
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Stem Cells in Leukemia: From Biological Properties to Therapeutic Targeting

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (29 May 2023) | Viewed by 26473

Special Issue Editor

Dr. Alice Giustacchini

E-Mail Website
Guest Editor
Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, London WC1N 1DZ, UK
Interests: hematopoiesis; myeloid leukemia; stem cells; cell heterogeneity; chimeric antigen receptors T cells

Special Issue Information

Dear Colleagues,

Understanding heterogeneity in cancer is becoming crucial for the development of effective therapeutic strategies. The proposed hierarchical structure of some tumors is one aspect of cancer heterogeneity, with “cancer stem-cells” (CSCs) being able to propagate the tumor and playing a role in tumor persistence and the development of therapy-resistance. Hematological malignancies have necessitated pioneering studies of CSCs, with leukemia stem cells (LSCs) being associated with unique intrinsic and extrinsic biological properties, making them selectively unresponsive to conventional therapies. This Special Issue will focus on the characterization of biological mechanisms responsible for therapy escape in LSCs and will touch upon novel therapeutic strategies accounting for the role of CSCs. 

Dr. Alice Giustacchini
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Published Papers (6 papers)

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Research

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12 pages, 1142 KiB  
Article
Survival after Pure (Acute) Erythroid Leukemia in the United States: A SEER-Based Study
by Kriti Gera, Daniela Martir, Wei Xue and John R. Wingard
Cancers 2023, 15(15), 3941; https://doi.org/10.3390/cancers15153941 - 3 Aug 2023
Cited by 4 | Viewed by 1529
Abstract
Background: Acute erythroid leukemia (AEL), also known as pure erythroid leukemia, is a rare subtype of acute myeloid leukemia (AML) characterized by the proliferation of malignant erythroid precursors. Outcome data at the population level are scarce. Methods: We performed a retrospective analysis of [...] Read more.
Background: Acute erythroid leukemia (AEL), also known as pure erythroid leukemia, is a rare subtype of acute myeloid leukemia (AML) characterized by the proliferation of malignant erythroid precursors. Outcome data at the population level are scarce. Methods: We performed a retrospective analysis of the Surveillance Epidemiology and End Results (SEER) database. All cases with a histologically confirmed diagnosis of acute (pure) erythroid leukemia during the period of 2000–2019 were included in the study. The Kaplan–Meier method was used to perform survival analysis. The significance of differences between overall survival (OS) was analyzed using the log-rank test. Results: In total, 968 patients were included in the study. The median age was 68 years (range 0–95), 62% of patients were males, and 62.5% (n = 605) were treated with chemotherapy. The median OS for <18, 18–49, 50–64, 65–79 and 80+ age groups was 69, 18, 8, 3 and 1 month, respectively (p < 0.0001). Patients who received chemotherapy had significantly improved OS compared to patients who did not, among both adults (p < 0.0001) and children (p = 0.004). There were no significant differences in OS based on sex, race, ethnicity and median household income. Median OS for adults diagnosed in 2000–2004, 2005–2009, 2010–2014, 2015–2019 was 4, 6, 6 and 3 months, respectively, with no significant differences in OS between these groups. Conclusion: AEL occurs in all age groups but is most common in the elderly. Outcomes are poor with current chemotherapeutic agents, with no improvement in the last two decades. This study stresses the urgent need for investigational agents. Full article
(This article belongs to the Special Issue Stem Cells in Leukemia: From Biological Properties to Therapeutic Targeting)
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16 pages, 3003 KiB  
Article
Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia
by Ryan J. Summers, Juhi Jain, Eleana Vasileiadi, Brittany Smith, Madison L. Chimenti, Tsz Y. Yeung, James Kelvin, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Jeffrey W. Tyner, Erik C. Dreaden, Deborah DeRyckere and Douglas K. Graham
Cancers 2022, 14(24), 6142; https://doi.org/10.3390/cancers14246142 - 13 Dec 2022
Cited by 3 | Viewed by 2656
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of childhood ALL. The early T-precursor (ETP-ALL) subset is characterized by an immature T-cell phenotype, chemoresistance, and high rates of induction failure. MERTK receptor tyrosine kinase is ectopically expressed in half of T-ALLs, particularly those [...] Read more.
T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of childhood ALL. The early T-precursor (ETP-ALL) subset is characterized by an immature T-cell phenotype, chemoresistance, and high rates of induction failure. MERTK receptor tyrosine kinase is ectopically expressed in half of T-ALLs, particularly those with an immature T-cell phenotype, suggesting a role in ETP-ALL. The anti-apoptotic protein B-cell lymphoma-2 (BCL-2) is essential for ETP-ALL cell survival. Here, we show that MERTK and BCL-2 mRNA and protein are preferentially expressed in ETP-ALL patient samples. The dual MERTK/FLT3 inhibitor MRX-2843 decreased MERTK activation and downstream signaling, inhibited cell expansion, and induced cell death in ETP-ALL cell lines. Further, 54% (21/39) of primary T-ALL patient samples were sensitive to MERTK inhibition. Treatment with MRX-2843 significantly reduced leukemia burden and prolonged survival in cell-line-derived T-ALL and ETP-ALL xenograft models. In a patient-derived ETP-ALL xenograft model, treatment with MRX-2843 markedly reduced peripheral blood leukemia and spleen weight compared to vehicle-treated mice and prolonged survival. MRX-2843 also synergized with venetoclax to provide enhanced anti-leukemia activity in ETP-ALL cell cultures, with a dose ratio of 1:20 MRX-2843:venetoclax providing optimal synergy. These data demonstrate the therapeutic potential of MRX-2843 in patients with T-ALL and provide rationale for clinical development. MRX-2843 monotherapy is currently being tested in patients with relapsed leukemia (NCT04872478). Further, our data indicate that combined MERTK and BCL-2 inhibition may be particularly effective for treatment of ETP-ALL. Full article
(This article belongs to the Special Issue Stem Cells in Leukemia: From Biological Properties to Therapeutic Targeting)
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18 pages, 3680 KiB  
Article
Tyrosine Kinase Inhibitor Independent Gene Expression Signature in CML Offers New Targets for LSPC Eradication Therapy
by Eduardo Gómez-Castañeda, Lisa E. M. Hopcroft, Simon Rogers, Chinmay Munje, Joana Bittencourt-Silvestre, Mhairi Copland, David Vetrie, Tessa Holyoake and Heather G. Jørgensen
Cancers 2022, 14(21), 5253; https://doi.org/10.3390/cancers14215253 - 26 Oct 2022
Viewed by 2276
Abstract
Tyrosine kinase inhibitors (TKI) have revolutionised the treatment of CML. However, TKI do not eliminate the leukaemia stem cells (LSC), which can re-initiate the disease. Thus, finding new therapeutic targets in CML LSC is key to finding a curative treatment. Using microarray datasets, [...] Read more.
Tyrosine kinase inhibitors (TKI) have revolutionised the treatment of CML. However, TKI do not eliminate the leukaemia stem cells (LSC), which can re-initiate the disease. Thus, finding new therapeutic targets in CML LSC is key to finding a curative treatment. Using microarray datasets, we defined a list of 227 genes that were differentially expressed in CML LSC compared to the healthy controls but were not affected by TKI in vitro. Two of them, CD33 and PPIF, are targeted by gemtuzumab–ozogamicin and cyclosporin A, respectively. We treated CML and the control CD34+ cells with either drug with or without imatinib to investigate the therapeutic potential of the TKI-independent gene expression programme. Cyclosporine A, in combination with imatinib, reduced the number of CML CFC compared with non-CML controls, but only at supra-therapeutic concentrations. Gemtuzumab–ozogamicin showed an EC50 of 146 ng/mL, below the plasma peak concentration of 630 ng/mL observed in the AML patients and below the EC50 of 3247 ng/mL observed in the non-CML cells. Interestingly, gemtuzumab–ozogamicin seems to promote cell cycle progression in CML CD34+ cells and demonstrated activation of the RUNX1 pathway in an RNAseq experiment. This suggests that targeting the TKI-independent genes in CML LSC could be exploited for the development of new therapies in CML. Full article
(This article belongs to the Special Issue Stem Cells in Leukemia: From Biological Properties to Therapeutic Targeting)
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Review

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30 pages, 937 KiB  
Review
Advances and Hurdles in CAR T Cell Immune Therapy for Solid Tumors
by Francesco Boccalatte, Roberto Mina, Andrea Aroldi, Sarah Leone, Carter M. Suryadevara, Dimitris G. Placantonakis and Benedetto Bruno
Cancers 2022, 14(20), 5108; https://doi.org/10.3390/cancers14205108 - 18 Oct 2022
Cited by 15 | Viewed by 3949
Abstract
Chimeric antigen receptor (CAR) T cells in solid tumors have so far yielded limited results, in terms of therapeutic effects, as compared to the dramatic results observed for hematological malignancies. Many factors involve both the tumor cells and the microenvironment. The lack of [...] Read more.
Chimeric antigen receptor (CAR) T cells in solid tumors have so far yielded limited results, in terms of therapeutic effects, as compared to the dramatic results observed for hematological malignancies. Many factors involve both the tumor cells and the microenvironment. The lack of specific target antigens and severe, potentially fatal, toxicities caused by on-target off-tumor toxicities constitute major hurdles. Furthermore, the tumor microenvironment is usually characterized by chronic inflammation, the presence of immunosuppressive molecules, and immune cells that can reduce CAR T cell efficacy and facilitate antigen escape. Nonetheless, solid tumors are under investigation as possible targets despite their complexity, which represents a significant challenge. In preclinical mouse models, CAR T cells are able to efficiently recognize and kill several tumor xenografts. Overall, in the next few years, there will be intensive research into optimizing novel cell therapies to improve their effector functions and keep untoward effects in check. In this review, we provide an update on the state-of-the-art CAR T cell therapies in solid tumors, focusing on the preclinical studies and preliminary clinical findings aimed at developing optimal strategies to reduce toxicity and improve efficacy. Full article
(This article belongs to the Special Issue Stem Cells in Leukemia: From Biological Properties to Therapeutic Targeting)
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33 pages, 1908 KiB  
Review
Isolation, Maintenance and Expansion of Adult Hematopoietic Stem/Progenitor Cells and Leukemic Stem Cells
by Isabella Maria Mayer, Andrea Hoelbl-Kovacic, Veronika Sexl and Eszter Doma
Cancers 2022, 14(7), 1723; https://doi.org/10.3390/cancers14071723 - 28 Mar 2022
Cited by 8 | Viewed by 6969
Abstract
Hematopoietic stem cells (HSCs) are rare, self-renewing cells that perch on top of the hematopoietic tree. The HSCs ensure the constant supply of mature blood cells in a tightly regulated process producing peripheral blood cells. Intense efforts are ongoing to optimize HSC engraftment [...] Read more.
Hematopoietic stem cells (HSCs) are rare, self-renewing cells that perch on top of the hematopoietic tree. The HSCs ensure the constant supply of mature blood cells in a tightly regulated process producing peripheral blood cells. Intense efforts are ongoing to optimize HSC engraftment as therapeutic strategy to treat patients suffering from hematopoietic diseases. Preclinical research paves the way by developing methods to maintain, manipulate and expand HSCs ex vivo to understand their regulation and molecular make-up. The generation of a sufficient number of transplantable HSCs is the Holy Grail for clinical therapy. Leukemia stem cells (LSCs) are characterized by their acquired stem cell characteristics and are responsible for disease initiation, progression, and relapse. We summarize efforts, that have been undertaken to increase the number of long-term (LT)-HSCs and to prevent differentiation towards committed progenitors in ex vivo culture. We provide an overview and compare methods currently available to isolate, maintain and enrich HSC subsets, progenitors and LSCs and discuss their individual advantages and drawbacks. Full article
(This article belongs to the Special Issue Stem Cells in Leukemia: From Biological Properties to Therapeutic Targeting)
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21 pages, 1159 KiB  
Review
Driving CAR T Stem Cell Targeting in Acute Myeloid Leukemia: The Roads to Success
by Ilaria M. Michelozzi, Efstratios Kirtsios and Alice Giustacchini
Cancers 2021, 13(11), 2816; https://doi.org/10.3390/cancers13112816 - 5 Jun 2021
Cited by 11 | Viewed by 6908
Abstract
Current treatment outcome for acute myeloid leukemia (AML) patients is unsatisfactory and characterized by high rates of relapse and poor overall survival. Increasing evidence points to a crucial role of leukemic stem cells (LSC) and the bone marrow (BM) leukemic niche, in which [...] Read more.
Current treatment outcome for acute myeloid leukemia (AML) patients is unsatisfactory and characterized by high rates of relapse and poor overall survival. Increasing evidence points to a crucial role of leukemic stem cells (LSC) and the bone marrow (BM) leukemic niche, in which they reside, in AML evolution and chemoresistance. Thus, future strategies aiming at improving AML therapeutic protocols are likely to be directed against LSC and their niche. Chimeric antigen receptor (CAR) T-cells have been extremely successful in the treatment of relapsed/refractory acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma and comparable results in AML are highly desirable. At present, we are at the dawn of CAR T-cell application in AML, with several preclinical studies and few early phase clinical trials. However, the lack of leukemia-specific targets and the genetic and phenotypic heterogeneity of the disease combined with the leukemia-induced remodeling of the BM microenvironment are limiting CAR T-cell exploitation in AML. Here, we reviewed AML-LSC and AML-BM niche features in the context of their therapeutic targeting using CAR T-cells. We summarized recent progress in CAR T-cell application to the treatment of AML, and we discussed the remaining therapeutic challenges and promising novel strategies to overcome them. Full article
(This article belongs to the Special Issue Stem Cells in Leukemia: From Biological Properties to Therapeutic Targeting)
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