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11 pages, 1078 KiB

Open AccessArticle

Clinical Implications of Discordant Early Molecular Responses in CML Patients Treated with Imatinib

by Stefania Stella, Valentina Zammit, Silvia Rita Vitale, Maria Stella Pennisi, Michele Massimino, Elena Tirrò, Stefano Forte, Antonio Spitaleri, Agostino Antolino, Sergio Siracusa, Vincenzo Accurso, Donato Mannina, Stefana Impera, Caterina Musolino, Sabina Russo, Alessandra Malato, Giuseppe Mineo, Maurizio Musso, Ferdinando Porretto, Bruno Martino, Francesco Di Raimondo, Livia Manzella, Paolo Vigneri and Fabio Stagno Show full author list Hide full author list

Int. J. Mol. Sci. 2019, 20(9), 2226; https://doi.org/10.3390/ijms20092226 - 6 May 2019

Cited by 17 | Viewed by 3581

Abstract

A reduction in BCR-ABL1/ABL1^IS transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple [...] Read more.

A reduction in BCR-ABL1/ABL1^IS transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1^IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR⁴; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1^IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3- and 6-month time points. Among these patients, those with BCR-ABL1/ABL1^IS values >10% at 3 months but <1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1^IS <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1^IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR⁴ compared to patients with BCR-ABL1/ABL1^IS <10% at 3 months but >1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUS^IS transcripts at diagnosis were associated with BCR-ABL1/ABL1^IS values <1% at 6 months (p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1^IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias)

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18 pages, 5089 KiB

Open AccessArticle

Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations—Possible Therapeutic Efficacy of Cabozantinib

by Ya-Chen Ko, Chung-Yi Hu, Zheng-Hau Liu, Hwei-Fang Tien, Da-Liang Ou, Hsiung-Fei Chien and Liang-In Lin

Int. J. Mol. Sci. 2019, 20(5), 1230; https://doi.org/10.3390/ijms20051230 - 11 Mar 2019

Cited by 7 | Viewed by 4944

Abstract

Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from FLT3-ITD-positive MV4-11 (MV4-11-P) cells and examine the development of resistance. The FLT3-ITD [...] Read more.

Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from FLT3-ITD-positive MV4-11 (MV4-11-P) cells and examine the development of resistance. The FLT3-ITD mutation was retained in MV4-11-R; however, the protein was underglycosylated and less phosphorylated in these cells. Moreover, the phosphorylation of ERK1/2, Akt, MEK1/2 and p53 increased in MV4-11-R. The levels of Mcl-1 and p53 proteins were also elevated in MV4-11-R. A p53 D281G mutant emerged in MV4-11-R, in addition to the pre-existing R248W mutation. MV4-11-P and MV4-11-R showed similar sensitivity to cabozantinib, sorafenib, and MK2206, whereas MV4-11-R showed resistance to CI-1040 and idarubicin. MV4-11-R resistance may be associated with inhibition of Akt phosphorylation, but not ERK phosphorylation, after exposure to these drugs. The multi-kinase inhibitor cabozantinib inhibited FLT3-ITD signaling in MV4-11-R cells and MV4-11-R-derived tumors in mice. Cabozantinib effectively inhibited tumor growth and prolonged survival time in mice bearing MV4-11-R-derived tumors. Together, our findings suggest that Mcl-1 and Akt phosphorylation are potential therapeutic targets for p53 mutants and that cabozantinib is an effective treatment in cytarabine-resistant FLT3-ITD-positive AML. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias)

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19 pages, 1632 KiB

Open AccessArticle

Bone Marrow Mast Cell Antibody-Targetable Cell Surface Protein Expression Profiles in Systemic Mastocytosis

by Noelia Dasilva-Freire, Andrea Mayado, Cristina Teodosio, María Jara-Acevedo, Iván Álvarez-Twose, Almudena Matito, Laura Sánchez-Muñoz, Carolina Caldas, Ana Henriques, Javier I. Muñoz-González, Andrés C. García-Montero, J. Ignacio Sánchez-Gallego, Luis Escribano and Alberto Orfao

Int. J. Mol. Sci. 2019, 20(3), 552; https://doi.org/10.3390/ijms20030552 - 28 Jan 2019

Cited by 10 | Viewed by 4936

Abstract

Despite recent therapeutic advances, systemic mastocytosis (SM) remains an incurable disease due to limited complete remission (CR) rates even after novel therapies. To date, no study has evaluated the expression on SM bone marrow mast cells (BMMC) of large panel of cell surface [...] Read more.

Despite recent therapeutic advances, systemic mastocytosis (SM) remains an incurable disease due to limited complete remission (CR) rates even after novel therapies. To date, no study has evaluated the expression on SM bone marrow mast cells (BMMC) of large panel of cell surface suitable for antibody-targeted therapy. In this study, we analyzed the expression profile of six cell-surface proteins for which antibody-based therapies are available, on BMMC from 166 SM patients vs. 40 controls. Overall, variable patterns of expression for the markers evaluated were observed among SM BMMC. Thus, CD22, CD30, and CD123, while expressed on BMMC from patients within every subtype of SM, showed highly variable patterns with a significant fraction of negative cases among advanced SM (aggressive SM (ASM), ASM with an associated clonal non-MC lineage disease (ASM-AHN) and MC leukemia (MCL)), 36%, 46%, and 39%, respectively. In turn, CD25 and FcεRI were found to be expressed in most cases (89% and 92%) in virtually all BMMC (median: 92% and 95%) from both indolent and advanced SM, but with lower/absent levels in a significant fraction of MC leukemia (MCL) and both in MCL and well-differentiated SM (WDSM) patients, respectively. In contrast, CD33 was the only marker expressed on all BMMC from every SM patient. Thus, CD33 emerges as the best potentially targetable cell-surface membrane marker in SM, particularly in advanced SM. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias)

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Review

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16 pages, 599 KiB

Open AccessReview

Minimal Residual Disease Monitoring with Next-Generation Sequencing Methodologies in Hematological Malignancies

by Ricardo Sánchez, Rosa Ayala and Joaquín Martínez-López

Int. J. Mol. Sci. 2019, 20(11), 2832; https://doi.org/10.3390/ijms20112832 - 10 Jun 2019

Cited by 40 | Viewed by 7092

Abstract

Ultra-deep next-generation sequencing has emerged in recent years as an important diagnostic tool for the detection and follow-up of tumor burden in most of the known hematopoietic malignancies. Meticulous and high-throughput methods for the lowest possible quantified disease are needed to address the [...] Read more.

Ultra-deep next-generation sequencing has emerged in recent years as an important diagnostic tool for the detection and follow-up of tumor burden in most of the known hematopoietic malignancies. Meticulous and high-throughput methods for the lowest possible quantified disease are needed to address the deficiencies of more classical techniques. Precision-based approaches will allow us to correctly stratify each patient based on the minimal residual disease (MRD) after a treatment cycle. In this review, we consider the most prominent ways to approach next-generation sequencing methodologies to follow-up MRD in hematological neoplasms. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias)

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10 pages, 227 KiB

Open AccessReview

Acute Myeloid Leukemia Mutations: Therapeutic Implications

by Cristina Papayannidis, Chiara Sartor, Giovanni Marconi, Maria Chiara Fontana, Jacopo Nanni, Gianluca Cristiano, Sarah Parisi, Stefania Paolini and Antonio Curti

Int. J. Mol. Sci. 2019, 20(11), 2721; https://doi.org/10.3390/ijms20112721 - 3 Jun 2019

Cited by 23 | Viewed by 3728

Abstract

Acute Myeloid Leukemia (AML) is an extremely heterogeneous group of hematological neoplasms, for which allogeneic stem cell transplantation (HSCT) still represents the only potentially curative option in the majority of cases. However, elderly age and clinically severe comorbidities may often exclude a wide [...] Read more.

Acute Myeloid Leukemia (AML) is an extremely heterogeneous group of hematological neoplasms, for which allogeneic stem cell transplantation (HSCT) still represents the only potentially curative option in the majority of cases. However, elderly age and clinically severe comorbidities may often exclude a wide amount of patients from this therapeutic approach, underlying the urgent need for alternative strategies. Thanks to the introduction of advanced high-throughput techniques, light is being shed on the pathogenesis of AML, identifying molecular recurrent mutations as responsible for the onset, as well as progression, of disease. As a consequence, and in parallel, many new compounds, including targeted therapies (FMS-like tyrosine kinase 3 (FLT3) and Isocitrate dehydrogenase 1-2 (IDH1-2) inhibitors), have found a wide room of application in this setting, and are now available in daily practice, or in late phases of clinical development. Moreover, several further innovative molecules are currently under investigation, and promising results for many of them have already been reported. In this review, we will present an update on the most relevant molecular alterations of AML, focusing on the most frequent genomic mutations of the disease, for which compounds have been approved or are still currently under investigation. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias)

14 pages, 576 KiB

Open AccessReview

Digital PCR in Myeloid Malignancies: Ready to Replace Quantitative PCR?

by Daniela Cilloni, Jessica Petiti, Valentina Rosso, Giacomo Andreani, Matteo Dragani, Carmen Fava and Giuseppe Saglio

Int. J. Mol. Sci. 2019, 20(9), 2249; https://doi.org/10.3390/ijms20092249 - 7 May 2019

Cited by 42 | Viewed by 7230

Abstract

New techniques are on the horizon for the detection of small leukemic clones in both, acute leukemias and myeloproliferative disorders. A promising approach is based on digital polymerase chain reaction (PCR). Digital PCR (dPCR) is a breakthrough technology designed to provide absolute nucleic [...] Read more.

New techniques are on the horizon for the detection of small leukemic clones in both, acute leukemias and myeloproliferative disorders. A promising approach is based on digital polymerase chain reaction (PCR). Digital PCR (dPCR) is a breakthrough technology designed to provide absolute nucleic acid quantification. It is particularly useful to detect a low amount of target and therefore it represents an alternative method for detecting measurable residual disease (MRD). The main advantages are the high precision, the very reliable quantification, the absolute quantification without the need for a standard curve, and the excellent reproducibility. Nowadays the main disadvantages of this strategy are the costs that are still higher than standard qPCR, the lack of standardized methods, and the limited number of laboratories that are equipped with instruments for dPCR. Several studies describing the possibility and advantages of using digital PCR for the detection of specific leukemic transcripts or mutations have already been published. In this review we summarize the available data on the use of dPCR in acute myeloid leukemia and myeloproliferative disorders. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias)

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19 pages, 862 KiB

Open AccessReview

New Targeted Agents in Acute Myeloid Leukemia: New Hope on the Rise

by Stephan R. Bohl, Lars Bullinger and Frank G. Rücker

Int. J. Mol. Sci. 2019, 20(8), 1983; https://doi.org/10.3390/ijms20081983 - 23 Apr 2019

Cited by 74 | Viewed by 7843

Abstract

The therapeutic approach for acute myeloid leukemia (AML) remains challenging, since over the last four decades a stagnation in standard cytotoxic treatment has been observed. But within recent years, remarkable advances in the understanding of the molecular heterogeneity and complexity of this disease [...] Read more.

The therapeutic approach for acute myeloid leukemia (AML) remains challenging, since over the last four decades a stagnation in standard cytotoxic treatment has been observed. But within recent years, remarkable advances in the understanding of the molecular heterogeneity and complexity of this disease have led to the identification of novel therapeutic targets. In the last two years, seven new targeted agents (midostaurin, gilteritinib, enasidenib, ivosidenib, glasdegib, venetoclax and gemtuzumab ozogamicin) have received US Food and Drug Administration (FDA) approval for the treatment of AML. These drugs did not just prove to have a clinical benefit as single agents but have especially improved AML patient outcomes if they are combined with conventional therapy. In this review, we will focus on currently approved and promising upcoming agents and we will discuss controversial aspects and limitations of targeted treatment strategies. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias)

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13 pages, 521 KiB

Open AccessReview

Blast Transformation in Myeloproliferative Neoplasms: Risk Factors, Biological Findings, and Targeted Therapeutic Options

by Alessandra Iurlo, Daniele Cattaneo and Umberto Gianelli

Int. J. Mol. Sci. 2019, 20(8), 1839; https://doi.org/10.3390/ijms20081839 - 13 Apr 2019

Cited by 52 | Viewed by 5622

Abstract

Myeloproliferative neoplasms represent a heterogenous group of disorders of the hematopoietic stem cell, with an intrinsic risk of evolution into acute myeloid leukemia. The frequency of leukemic evolution varies according to myeloproliferative neoplasms subtype. It is highest in primary myelofibrosis, where it is [...] Read more.

Myeloproliferative neoplasms represent a heterogenous group of disorders of the hematopoietic stem cell, with an intrinsic risk of evolution into acute myeloid leukemia. The frequency of leukemic evolution varies according to myeloproliferative neoplasms subtype. It is highest in primary myelofibrosis, where it is estimated to be approximately 10–20% at 10 years, following by polycythemia vera, with a risk of 2.3% at 10 years and 7.9% at 20 years. In essential thrombocythemia, however, transformation to acute myeloid leukemia is considered relatively uncommon. Different factors are associated with leukemic evolution in myeloproliferative neoplasms, but generally include advanced age, leukocytosis, exposure to myelosuppressive therapy, cytogenetic abnormalities, as well as increased number of mutations in genes associated with myeloid neoplasms. The prognosis of these patients is dismal, with a medium overall survival ranging from 2.6–7.0 months. Currently, there is no standard of care for managing the blast phase of these diseases, and no treatment to date has consistently led to prolonged survival and/or hematological remission apart from an allogeneic stem cell transplant. Nevertheless, new targeted agents are currently under development. In this review, we present the current evidence regarding risk factors, molecular characterization, and treatment options for this critical subset of myeloproliferative neoplasms patients. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias)

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21 pages, 1012 KiB

Open AccessReview

Antigen Targets for the Development of Immunotherapies in Leukemia

by Jens Bauer, Annika Nelde, Tatjana Bilich and Juliane S. Walz

Int. J. Mol. Sci. 2019, 20(6), 1397; https://doi.org/10.3390/ijms20061397 - 20 Mar 2019

Cited by 12 | Viewed by 6640

Abstract

Immunotherapeutic approaches, including allogeneic stem cell transplantation and donor lymphocyte infusion, have significantly improved the prognosis of leukemia patients. Further efforts are now focusing on the development of immunotherapies that are able to target leukemic cells more specifically, comprising monoclonal antibodies, chimeric antigen [...] Read more.

Immunotherapeutic approaches, including allogeneic stem cell transplantation and donor lymphocyte infusion, have significantly improved the prognosis of leukemia patients. Further efforts are now focusing on the development of immunotherapies that are able to target leukemic cells more specifically, comprising monoclonal antibodies, chimeric antigen receptor (CAR) T cells, and dendritic cell- or peptide-based vaccination strategies. One main prerequisite for such antigen-specific approaches is the selection of suitable target structures on leukemic cells. In general, the targets for anti-cancer immunotherapies can be divided into two groups: (1) T-cell epitopes relying on the presentation of peptides via human leukocyte antigen (HLA) molecules and (2) surface structures, which are HLA-independently expressed on cancer cells. This review discusses the most promising tumor antigens as well as the underlying discovery and selection strategies for the development of anti-leukemia immunotherapies. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias)

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