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Drug Resistance in Hematologic Malignancies

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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: closed (31 December 2019) | Viewed by 72542

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Special Issue Editors

Dr. Patrick Auberger

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Guest Editor

Team "Myeloid Malignancies and Multiple Myeloma", Université Côte d’Azur, Inserm U1065/C3M, 06204 Nice, France
Interests: Onco-Hematology; signaling; apoptosis; autophagy; resistance to Therapy; new therapeutic strategies

Prof. Dr. Jerome Tamburini-Bonnefoy

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Guest Editor

Cochin Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
Interests: Acute Myeloid Leukemia; signaling pathways; Drug resistance

Dr. Alexandre Puissant

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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

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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 (13 papers)

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Editorial

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2 pages, 154 KiB

Open AccessEditorial

Drug Resistance in Hematological Malignancies

by Patrick Auberger, Jerome Tamburini-Bonnefoy and Alexandre Puissant

Int. J. Mol. Sci. 2020, 21(17), 6091; https://doi.org/10.3390/ijms21176091 - 24 Aug 2020

Cited by 21 | Viewed by 2258

Abstract

Hematological malignancies define a highly heterogeneous set of blood-, bone marrow-, and organ-associated diseases with highly variable prognoses that constantly relapse upon treatment [...] Full article

(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)

Research

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13 pages, 2954 KiB

Open AccessArticle

Acadesine Circumvents Azacitidine Resistance in Myelodysplastic Syndrome and Acute Myeloid Leukemia

by Thomas Cluzeau, Nathan Furstoss, Coline Savy, Wejdane El Manaa, Marwa Zerhouni, Lauriane Blot, Anne Calleja, Maeva Dufies, Alix Dubois, Clemence Ginet, Nicolas Mounier, Georges Garnier, Sophie Raynaud, Pierre Simon Rohrlich, Pierre Peterlin, Aspasia Stamatoullas, Fatiha Chermat, Pierre Fenaux, Arnaud Jacquel, Guillaume Robert and Patrick Auberger Show full author list Hide full author list

Int. J. Mol. Sci. 2020, 21(1), 164; https://doi.org/10.3390/ijms21010164 - 25 Dec 2019

Cited by 8 | Viewed by 2798

Abstract

Myelodysplastic syndrome (MDS) defines a group of heterogeneous hematologic malignancies that often progresses to acute myeloid leukemia (AML). The leading treatment for high-risk MDS patients is azacitidine (Aza, Vidaza^®), but a significant proportion of patients are refractory and all patients eventually relapse after an undefined time period. Therefore, new therapies for MDS are urgently needed. We present here evidence that acadesine (Aca, Acadra^®), a nucleoside analog exerts potent anti-leukemic effects in both Aza-sensitive (OCI-M2S) and resistant (OCI-M2R) MDS/AML cell lines in vitro. Aca also exerts potent anti-leukemic effect on bone marrow cells from MDS/AML patients ex-vivo. The effect of Aca on MDS/AML cell line proliferation does not rely on apoptosis induction. It is also noteworthy that Aca is efficient to kill MDS cells in a co-culture model with human medullary stromal cell lines, that mimics better the interaction occurring in the bone marrow. These initial findings led us to initiate a phase I/II clinical trial using Acadra^® in 12 Aza refractory MDS/AML patients. Despite a very good response in one out 4 patients, we stopped this trial because the highest Aca dose (210 mg/kg) caused serious renal side effects in several patients. In conclusion, the side effects of high Aca doses preclude its use in patients with strong comorbidities. Full article

(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)

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15 pages, 3555 KiB

Open AccessArticle

Heterogeneous Pattern of Dependence on Anti-Apoptotic BCL-2 Family Proteins upon CHOP Treatment in Diffuse Large B-Cell Lymphoma

by Mathilde Rikje Willemijn de Jong, Myra Langendonk, Bart Reitsma, Marcel Nijland, Anke van den Berg, Emanuele Ammatuna, Lydia Visser and Tom van Meerten

Int. J. Mol. Sci. 2019, 20(23), 6036; https://doi.org/10.3390/ijms20236036 - 30 Nov 2019

Cited by 13 | Viewed by 3595

Abstract

Expression of the anti-apoptotic B-cell lymphoma 2 (BCL-2) protein in patients with diffuse large B-cell lymphoma (DLBCL) strongly correlates with resistance to standard therapy with cyclophosphamide, vincristine, doxorubicin, prednisolone, and rituximab (R-CHOP). Although studies focus mainly on the contribution of BCL-2, here we also investigate the contribution of other anti-apoptotic proteins to CHOP-therapy resistance in DLBCL. Functional dynamic BCL-2 homology (BH)3 profiling was applied to DLBCL cell lines upon CHOP treatment or single CHOP compounds. Cell-specific anti-apoptotic dependencies were validated with corresponding BH3-mimetics. We found high expression of anti-apoptotic BCL-2, MCL-1, and BCL-XL in DLBCL cell lines and patients. CHOP treatment resulted in both enhanced and altered anti-apoptotic dependency. Enhanced sensitivity to different BH3-mimetics after CHOP treatment was confirmed in specific cell lines, indicating heterogeneity of CHOP-induced resistance in DLBCL. Analysis of single CHOP compounds demonstrated that similar changes could also be induced by doxorubicin or vincristine, providing evidence for clinical combination therapies of doxorubicin or vincristine with BH3-mimetics in DLBCL. In conclusion, we show for the first time that CHOP treatment induces increased anti-apoptotic dependency on MCL-1 and BCL-XL, and not just BCL-2. These results provide new perspectives for the treatment of CHOP-resistant DLBCL and underline the potential of BH3 profiling in predicting therapy outcomes. Full article

(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)

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Review

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25 pages, 3751 KiB

Open AccessReview

Drug Resistance in Non-Hodgkin Lymphomas

by Pavel Klener and Magdalena Klanova

Int. J. Mol. Sci. 2020, 21(6), 2081; https://doi.org/10.3390/ijms21062081 - 18 Mar 2020

Cited by 35 | Viewed by 4922

Abstract

Non-Hodgkin lymphomas (NHL) are lymphoid tumors that arise by a complex process of malignant transformation of mature lymphocytes during various stages of differentiation. The WHO classification of NHL recognizes more than 90 nosological units with peculiar pathophysiology and prognosis. Since the end of the 20^th century, our increasing knowledge of the molecular biology of lymphoma subtypes led to the identification of novel druggable targets and subsequent testing and clinical approval of novel anti-lymphoma agents, which translated into significant improvement of patients’ outcome. Despite immense progress, our effort to control or even eradicate malignant lymphoma clones has been frequently hampered by the development of drug resistance with ensuing unmet medical need to cope with relapsed or treatment-refractory disease. A better understanding of the molecular mechanisms that underlie inherent or acquired drug resistance might lead to the design of more effective front-line treatment algorithms based on reliable predictive markers or personalized salvage therapy, tailored to overcome resistant clones, by targeting weak spots of lymphoma cells resistant to previous line(s) of therapy. This review focuses on the history and recent advances in our understanding of molecular mechanisms of resistance to genotoxic and targeted agents used in clinical practice for the therapy of NHL. Full article

(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)

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13 pages, 1287 KiB

Open AccessReview

Overcoming Resistance to FLT3 Inhibitors in the Treatment of FLT3-Mutated AML

by Stephen S.Y. Lam and Anskar Y.H. Leung

Int. J. Mol. Sci. 2020, 21(4), 1537; https://doi.org/10.3390/ijms21041537 - 24 Feb 2020

Cited by 36 | Viewed by 4828

Abstract

Acute myeloid leukaemia (AML) carrying internal tandem duplication (ITD) of Fms-Like Tyrosine kinase 3 (FLT3) gene is associated with high risk of relapse and poor clinical outcome upon treatment with conventional chemotherapy. FLT3 inhibitors have been approved for the treatment of this AML subtype but leukaemia relapse remains to be a major cause of treatment failure. Mechanisms of drug resistance have been proposed, including evolution of resistant leukaemic clones; adaptive cellular mechanisms and a protective leukaemic microenvironment. These models have provided important leads that may inform design of clinical trials. Clinically, FLT3 inhibitors in combination with conventional chemotherapy as induction treatment for fit patients; with low-intensity treatment as salvage treatment or induction for unfit patients as well as maintenance treatment with FLT3 inhibitors post HSCT hold promise to improve survival in this AML subtype. Full article

(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)

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19 pages, 1440 KiB

Open AccessReview

Impact and Intricacies of Bone Marrow Microenvironment in B-cell Lymphomas: From Biology to Therapy

by Anuvrat Sircar, Sayan Mullick Chowdhury, Amber Hart, William Connor Bell, Satishkumar Singh, Lalit Sehgal and Narendranath Epperla

Int. J. Mol. Sci. 2020, 21(3), 904; https://doi.org/10.3390/ijms21030904 - 30 Jan 2020

Cited by 13 | Viewed by 4551

Abstract

Lymphoma, a group of widely prevalent hematological malignancies of lymphocyte origin, has become the focus of significant clinical research due to their high propensity for refractory/relapsed (R/R) disease, leading to poor prognostic outcomes. The complex molecular circuitry in lymphomas, especially in the aggressive phenotypes, has made it difficult to find a therapeutic option that can salvage R/R disease. Furthermore, the association of lymphomas with the Bone Marrow (BM) microenvironment has been found to portend worse outcomes in terms of heightened chances of relapse and acquired resistance to chemotherapy. This review assesses the current therapy options in three distinct types of lymphomas: diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. It also explores the role of the BM tumor microenvironment as a secure ‘niche’ for lymphoma cells to grow, proliferate and survive. It further evaluates potential mechanisms through which the tumor cells can establish molecular connections with the BM cells to provide pro-tumor benefits, and discusses putative therapeutic strategies for disrupting the BM-lymphoma cell communication. Full article

(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)

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31 pages, 950 KiB

Open AccessReview

Druggable Biochemical Pathways and Potential Therapeutic Alternatives to Target Leukemic Stem Cells and Eliminate the Residual Disease in Chronic Myeloid Leukemia

by Fabien Muselli, Jean-François Peyron and Didier Mary

Int. J. Mol. Sci. 2019, 20(22), 5616; https://doi.org/10.3390/ijms20225616 - 10 Nov 2019

Cited by 20 | Viewed by 5482

Abstract

Chronic Myeloid Leukemia (CML) is a disease arising in stem cells expressing the BCR-ABL oncogenic tyrosine kinase that transforms one Hematopoietic stem/progenitor Cell into a Leukemic Stem Cell (LSC) at the origin of differentiated and proliferating leukemic cells in the bone marrow (BM). CML-LSCs are recognized as being responsible for resistances and relapses that occur despite the advent of BCR-ABL-targeting therapies with Tyrosine Kinase Inhibitors (TKIs). LSCs share a lot of functional properties with Hematopoietic Stem Cells (HSCs) although some phenotypical and functional differences have been described during the last two decades. Subverted mechanisms affecting epigenetic processes, apoptosis, autophagy and more recently metabolism and immunology in the bone marrow microenvironment (BMM) have been reported. The aim of this review is to bring together the modifications and molecular mechanisms that are known to account for TKI resistance in primary CML-LSCs and to focus on the potential solutions that can circumvent these resistances, in particular those that have been, or will be tested in clinical trials. Full article

(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)

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17 pages, 779 KiB

Open AccessReview

Resistance Mechanisms to CAR T-Cell Therapy and Overcoming Strategy in B-Cell Hematologic Malignancies

by Moo-Kon Song, Byeong-Bae Park and Ji-Eun Uhm

Int. J. Mol. Sci. 2019, 20(20), 5010; https://doi.org/10.3390/ijms20205010 - 10 Oct 2019

Cited by 32 | Viewed by 9199

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 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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18 pages, 2661 KiB

Open AccessReview

The SUMO Pathway in Hematomalignancies and Their Response to Therapies

by Mathias Boulanger, Rosa Paolillo, Marc Piechaczyk and Guillaume Bossis

Int. J. Mol. Sci. 2019, 20(16), 3895; https://doi.org/10.3390/ijms20163895 - 09 Aug 2019

Cited by 28 | Viewed by 6366

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 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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9 pages, 580 KiB

Open AccessReview

Setting Fire to ESA and EMA Resistance: New Targeted Treatment Options in Lower Risk Myelodysplastic Syndromes

by Anne Sophie Kubasch and Uwe Platzbecker

Int. J. Mol. Sci. 2019, 20(16), 3853; https://doi.org/10.3390/ijms20163853 - 07 Aug 2019

Cited by 18 | Viewed by 5387

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 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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16 pages, 1539 KiB

Open AccessReview

Autophagy: New Insights into Mechanisms of Action and Resistance of Treatment in Acute Promyelocytic leukemia

by Mohammad Amin Moosavi and Mojgan Djavaheri-Mergny

Int. J. Mol. Sci. 2019, 20(14), 3559; https://doi.org/10.3390/ijms20143559 - 20 Jul 2019

Cited by 39 | Viewed by 7952

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 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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17 pages, 686 KiB

Open AccessReview

Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?

by Solène Fernandez, Vanessa Desplat, Arnaud Villacreces, Amélie V. Guitart, Noël Milpied, Arnaud Pigneux, Isabelle Vigon, Jean-Max Pasquet and Pierre-Yves Dumas

Int. J. Mol. Sci. 2019, 20(14), 3429; https://doi.org/10.3390/ijms20143429 - 12 Jul 2019

Cited by 33 | Viewed by 6131

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 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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28 pages, 2180 KiB

Open AccessReview

Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia

by Elena Follini, Matteo Marchesini and Giovanni Roti

Int. J. Mol. Sci. 2019, 20(12), 3021; https://doi.org/10.3390/ijms20123021 - 20 Jun 2019

Cited by 53 | Viewed by 8344

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 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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