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Special Issue "Drug Resistance in Hematologic Malignancies"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 31 December 2019.

Special Issue Editors

Dr. Patrick Auberger
E-Mail Website
Guest Editor
Centre Mediterraneen de Medecine Moleculaire, Nice, France
Interests: cancer; oncohematology; cell death; autophagy; signaling pathways; resistance to therapies
Prof. Dr. Jerome Tamburini-Bonnefoy
E-Mail
Guest Editor
Cochin Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
Interests: Acute Myeloid Leukemia; signaling pathways; Drug resistance
Dr. Alexandre Puissant
E-Mail Website
Guest Editor
INSERM U944, Hôpital St Louis, France
Interests: Acute Myeloid Leukemia; High-Throughput Screening; Chemoresistance; Syngeneic Mouse Models

Special Issue Information

Dear Colleagues,

Resistance to therapies is a hallmark and major drawback of all cancers. Hematological malignancies define a highly heterogeneous set of blood, bone marrow, and organ-associated diseases with highly variable prognosis that constantly relapse upon treatment. Although some of these diseases, such as Chronic Myelogenous Leukemia (CML), are now almost always curable thanks to targeted therapies, many others remain a major public health concern. Nevertheless, considerable progresses have been made in the management of patients suffering from hematological malignancies in these past ten years, and patients now beneficiate from a plethora of treatments, from conventional to targeted and immunotherapies. Whatever the kind of treatment, malignant hematopoietic cells consistently develop cellular strategies to adapt and survive to therapeutic drugs. Such an adaptation may involve different molecular and cellular mechanisms, including the acquisition of mutations. In addition, the modulation of the signaling pathways involved in apoptosis, autophagy, proliferation, proteostasis, metabolism, epigenetic modifications, and the modulation of oncogenes or tumor suppressors represent additional processes which may lead to therapy-induced resistance. Other potential mechanisms of resistance arise from the tumor stromal niche, for instance, through cytokines and growth factors production or exosome secretion. This Special Issue of IJMS will encompass the ensemble of the resistance processes set up in the course of hematological malignancies treatment and the mechanisms by which alterations of these pathways can be therapeutically exploited to improve therapies.

Dr. Patrick Auberger
Prof. Dr. Jerome Tamburini-Bonnefoy
Dr. Alexandre Puissant
Guest Editors

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 papers will be 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 short 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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Blood and Bone Marrow Cancers
  • Leukemia
  • Lymphoma
  • Myeloma
  • Resistance to Therapy
  • Conventional, Targeted and Immunotherapies
  • Apoptosis
  • Autophagy
  • Proteostasis
  • Metabolism
  • Cell Signalling
  • Cytokines/Growth Factors
  • Oncogenes/Tumor Suppressors
  • Organelle biogenesis
  • Exosomes

Published Papers (6 papers)

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Review

Open AccessReview
Resistance Mechanisms to CAR T-Cell Therapy and Overcoming Strategy in B-Cell Hematologic Malignancies
Int. J. Mol. Sci. 2019, 20(20), 5010; https://doi.org/10.3390/ijms20205010 - 10 Oct 2019
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has shown promising clinical impact against hematologic malignancies. CD19 is a marker on the surface of normal B cells as well as most B-cell malignancies, and thus has a role as an effective target for CAR T-cell [...] Read more.
Chimeric antigen receptor (CAR) T-cell therapy has shown promising clinical impact against hematologic malignancies. CD19 is a marker on the surface of normal B cells as well as most B-cell malignancies, and thus has a role as an effective target for CAR T-cell therapy. In numerous clinical data, successes with cell therapy have provided anticancer therapy as a potential therapeutic option for patients who are resistant to standard chemotherapies. However, recent growing evidence showed the limitations of the treatment such as antigen-positive relapse due to poor CAR T-cell persistence and antigen-negative relapses associated with CAR-driven mutations, alternative splicing, epitope masking, low antigen density, and lineage switching. The understanding of the resistance mechanisms to the cell therapy has developed novel potential treatment strategies, including dual-targeting therapy (dual and tandem CAR), and armored and universal CAR T-cell therapies. In this review, we provide an overview of resistance mechanisms to CD19 CAR T-cell therapy in B-cell malignancies and also review therapeutic strategies to overcome these resistances. Full article
(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)
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Open AccessReview
The SUMO Pathway in Hematomalignancies and Their Response to Therapies
Int. J. Mol. Sci. 2019, 20(16), 3895; https://doi.org/10.3390/ijms20163895 - 09 Aug 2019
Abstract
SUMO (Small Ubiquitin-related MOdifier) is a post-translational modifier of the ubiquitin family controlling the function and fate of thousands of proteins. SUMOylation is deregulated in various hematological malignancies, where it participates in both tumorigenesis and cancer cell response to therapies. This is the [...] Read more.
SUMO (Small Ubiquitin-related MOdifier) is a post-translational modifier of the ubiquitin family controlling the function and fate of thousands of proteins. SUMOylation is deregulated in various hematological malignancies, where it participates in both tumorigenesis and cancer cell response to therapies. This is the case for Acute Promyelocytic Leukemias (APL) where SUMOylation, and subsequent destruction, of the PML-RARα fusion oncoprotein are triggered by arsenic trioxide, which is used as front-line therapy in combination with retinoic acid to cure APL patients. A similar arsenic-induced SUMO-dependent degradation was also documented for Tax, a human T-cell lymphotropic virus type I (HTLV1) viral protein implicated in Adult T-cell Leukemogenesis. SUMOylation also participates in Acute Myeloid Leukemia (AML) response to both chemo- and differentiation therapies, in particular through its ability to regulate gene expression. In Multiple Myeloma, many enzymes of the SUMO pathway are overexpressed and their high expression correlates with lower response to melphalan-based chemotherapies. B-cell lymphomas overexpressing the c-Myc oncogene also overexpress most components of the SUMO pathway and are highly sensitive to SUMOylation inhibition. Targeting the SUMO pathway with recently discovered pharmacological inhibitors, alone or in combination with current therapies, might therefore constitute a powerful strategy to improve the treatment of these cancers. Full article
(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)
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Open AccessReview
Setting Fire to ESA and EMA Resistance: New Targeted Treatment Options in Lower Risk Myelodysplastic Syndromes
Int. J. Mol. Sci. 2019, 20(16), 3853; https://doi.org/10.3390/ijms20163853 - 07 Aug 2019
Abstract
During the last decade, substantial advances have been made in the understanding of the complex molecular, immunological and cellular disturbances involved in the initiation as well as evolution of myelodysplastic syndromes (MDS). In 85% of the mainly frail and older patient population, anemia [...] Read more.
During the last decade, substantial advances have been made in the understanding of the complex molecular, immunological and cellular disturbances involved in the initiation as well as evolution of myelodysplastic syndromes (MDS). In 85% of the mainly frail and older patient population, anemia is present at the time of diagnosis and is thus a major therapeutic challenge. High rates of primary resistance to erythropoiesis-stimulating agents (ESAs), the currently only approved standard therapy to treat anemia in lower-risk MDS, demand the development of novel and efficient drugs with a good safety profile. Luspatercept, a ligand trap of activin receptor II, is able to promote late stage erythropoiesis even in patients failing prior ESA treatment. The presence of ring sideroblastic phenotype defines a subgroup of patients with higher response rates. Additionally, recent developments in clinical research using HIF-1 or telomerase modulation by roxadustat or imetelstat are promising. Other areas of translational research involve targeting the inflammasome by anti-inflammatory drugs in order to improve anemia. These efforts will hopefully pave the way for new targeted treatment options for anemic low-risk MDS patients. Full article
(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)
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Open AccessReview
Autophagy: New Insights into Mechanisms of Action and Resistance of Treatment in Acute Promyelocytic leukemia
Int. J. Mol. Sci. 2019, 20(14), 3559; https://doi.org/10.3390/ijms20143559 - 20 Jul 2019
Cited by 1
Abstract
Autophagy is one of the main cellular catabolic pathways controlling a variety of physiological processes, including those involved in self-renewal, differentiation and death. While acute promyelocytic leukemia (APL) cells manifest low levels of expression of autophagy genes associated with reduced autophagy activity, the [...] Read more.
Autophagy is one of the main cellular catabolic pathways controlling a variety of physiological processes, including those involved in self-renewal, differentiation and death. While acute promyelocytic leukemia (APL) cells manifest low levels of expression of autophagy genes associated with reduced autophagy activity, the introduction of all-trans retinoid acid (ATRA)—a differentiating agent currently used in clinical settings—restores autophagy in these cells. ATRA-induced autophagy is involved in granulocytes differentiation through a mechanism that involves among others the degradation of the PML-RARα oncoprotein. Arsenic trioxide (ATO) is another anti-cancer agent that promotes autophagy-dependent clearance of promyelocytic leukemia retinoic acid receptor alpha gene (PML-RARα) in APL cells. Hence, enhancing autophagy may have therapeutic benefits in maturation-resistant APL cells. However, the role of autophagy in response to APL therapy is not so simple, because some autophagy proteins have been shown to play a pro-survival role upon ATRA and ATO treatment, and both agents can activate ETosis, a type of cell death mediated by the release of neutrophil extracellular traps (ETs). This review highlights recent findings on the impact of autophagy on the mechanisms of action of ATRA and ATO in APL cells. We also discuss the potential role of autophagy in the development of resistance to treatment, and of differentiation syndrome in APL. Full article
(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)
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Open AccessReview
Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?
Int. J. Mol. Sci. 2019, 20(14), 3429; https://doi.org/10.3390/ijms20143429 - 12 Jul 2019
Cited by 1
Abstract
Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical “3 + 7” treatment (cytarabine and daunorubicin) is currently [...] Read more.
Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical “3 + 7” treatment (cytarabine and daunorubicin) is currently challenged by new therapeutic strategies, including drugs depending on the molecular landscape of AML. This panel of mutations makes it possible to combine some of these new treatments with conventional chemotherapy. For example, the FLT3 receptor is overexpressed or mutated in 80% or 30% of AML, respectively. Such anomalies have led to the development of targeted therapies using tyrosine kinase inhibitors (TKIs). In this review, we document the history of TKI targeting, FLT3 and several other tyrosine kinases involved in dysregulated signaling pathways. Full article
(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)
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Open AccessReview
Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia
Int. J. Mol. Sci. 2019, 20(12), 3021; https://doi.org/10.3390/ijms20123021 - 20 Jun 2019
Cited by 2
Abstract
Chemoresistance is a major cause of recurrence and death from T-cell acute lymphoblastic leukemia (T-ALL), both in adult and pediatric patients. In the majority of cases, drug-resistant disease is treated by selecting a combination of other drugs, without understanding the molecular mechanisms by [...] Read more.
Chemoresistance is a major cause of recurrence and death from T-cell acute lymphoblastic leukemia (T-ALL), both in adult and pediatric patients. In the majority of cases, drug-resistant disease is treated by selecting a combination of other drugs, without understanding the molecular mechanisms by which malignant cells escape chemotherapeutic treatments, even though a more detailed genomic characterization and the identification of actionable disease targets may enable informed decision of new agents to improve patient outcomes. In this work, we describe pathways of resistance to common chemotherapeutic agents including glucocorticoids and review the resistance mechanisms to targeted therapy such as IL7R, PI3K-AKT-mTOR, NOTCH1, BRD4/MYC, Cyclin D3: CDK4/CDK6, BCL2 inhibitors, and selective inhibitors of nuclear export (SINE). Finally, to overcome the limitations of the current trial-and-error method, we summarize the experiences of anti-cancer drug sensitivity resistance profiling (DSRP) approaches as a rapid and relevant strategy to infer drug activity and provide functional information to assist clinical decision one patient at a time. Full article
(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

  • Mechanisms of Resistance to Ibrutinib in Lymphoid Malignancies
  • Mechanisms of Evasion to TKI in CML
  • Mechanism of Resistance in T-ALL and ETP- ALL
  • Resistance and Escape to Anti-CD19 Immunotherapies in ALL
  • HMA Resistance in MDS and AML
  • Resistance to ESA and EMA in MDS
  • Acadesine Circumvents Azacitidine Resistance in Myelodysplastic Syndrome and Acute Myeloid Leukemia
  • Mechanisms of Drug Resistance in FLT3 Mutant AML
  • Transcriptional and Epigenetic Cell States Mediating Therapeutic Resistance and Minimal Residual Disease in B Cell Malignancies
  • Role of Autophagy in Drug Resistance of Acute Promyelocytic Leukemia
  • ITK in AML Treatment
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