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Open AccessEditorial

Chronic Myeloid Leukemia in Children and Adolescents: The Achilles Heel of Oncogenesis and Tyrosine Kinase Inhibitors

by Maria Moschovi and Charikleia Kelaidi

Int. J. Mol. Sci. 2021, 22(15), 7806; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157806 - 21 Jul 2021

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Abstract

Chronic myeloid leukemia (CML) is a rare disease in children and adolescents [...] Full article

(This article belongs to the Special Issue Hematological Malignancies)

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Research

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13 pages, 2645 KiB

Open AccessArticle

Rationale for a Combination Therapy with the STAT5 Inhibitor AC-4-130 and the MCL1 Inhibitor S63845 in the Treatment of FLT3-Mutated or TET2-Mutated Acute Myeloid Leukemia

by Katja Seipel, Carolyn Graber, Laura Flückiger, Ulrike Bacher and Thomas Pabst

Int. J. Mol. Sci. 2021, 22(15), 8092; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158092 - 28 Jul 2021

Cited by 6 | Viewed by 2569

Abstract

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with de novo acute myeloid leukemia (AML). Mutated FLT3 variants are constitutively active kinases signaling via AKT kinase, MAP kinases, and STAT5. FLT3 inhibitors have been approved for [...] Read more.

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with de novo acute myeloid leukemia (AML). Mutated FLT3 variants are constitutively active kinases signaling via AKT kinase, MAP kinases, and STAT5. FLT3 inhibitors have been approved for the treatment of FLT3-mutated AML. However, treatment response to FLT3 inhibitors may be short-lived, and resistance may emerge. Compounds targeting STAT5 may enhance and prolong effects of FLT3 inhibitors in this subset of patients with FLT3-mutated AML. Here STAT5-inhibitor AC-4-130, FLT3 inhibitor midostaurin (PKC412), BMI-1 inhibitor PTC596, MEK-inhibitor trametinib, MCL1-inhibitor S63845, and BCL-2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. Synergistic effects on cell viability were detected in both FLT3-mutated and FLT3-wild-type AML cells treated with AC-4-130 in combination with the MCL1 inhibitor S63845. AML patient samples with a strong response to AC-4-130 and S63845 combination treatment were characterized by mutated FLT3 or mutated TET2 genes. Susceptibility of AML cells to AC-4-130, PTC596, trametinib, PKC412, and venetoclax was altered in the presence of HS-5 stroma. Only the MCL1 inhibitor S63845 induced cell death with equal efficacy in the absence or presence of bone marrow stroma. The combination of the STAT5-inhibitor AC-4-130 and the MCL1 inhibitor S63845 may be an effective treatment targeting FLT3-mutated or TET2-mutated AML. Full article

(This article belongs to the Special Issue Hematological Malignancies)

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16 pages, 5576 KiB

Open AccessArticle

Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes

by Cristina Martínez-Valiente, Cristian Garcia-Ruiz, Beatriz Rosón, Alessandro Liquori, Elisa González-Romero, Raúl Fernández-González, Isabel Gómez-Redondo, José Cervera, Alfonso Gutiérrez-Adán and Alejandra Sanjuan-Pla

Int. J. Mol. Sci. 2021, 22(13), 6963; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136963 - 28 Jun 2021

Cited by 5 | Viewed by 3100

Abstract

Mutations in splicing factors are recurrent somatic alterations identified in myelodysplastic syndromes (MDS) and they frequently coincide with mutations in epigenetic factors. About 25% of patients present concurrent mutations in such pathways, suggesting a cooperative role in the pathogenesis of MDS. We focused [...] Read more.

Mutations in splicing factors are recurrent somatic alterations identified in myelodysplastic syndromes (MDS) and they frequently coincide with mutations in epigenetic factors. About 25% of patients present concurrent mutations in such pathways, suggesting a cooperative role in the pathogenesis of MDS. We focused on the splicing factor U2AF1 involved in the recognition of the 3′ splice site during pre-mRNA splicing. Using a CRISPR/Cas9 system, we created heterozygous mice with a carboxy-terminal truncated U2af1 allele (U2af1^mut/+), studied the U2af1^mut/+ hematopoietic system, and did not observe any gross differences in both young (12–13 weeks) and old (23 months) U2af1^mut/+ mice, except for a reduction in size of approximately 20%. However, hematopoietic stem/progenitor cells lacked reconstitution capacity in transplantation assays and displayed an aberrant RNA splicing by RNA sequencing. We also evaluated U2af1^mut/+ in conjunction with Tet2-deficiency. Novel double mutant U2af1^mut/+Tet2^−/− mice showed increased monogranulocytic precursors. Hematopoietic stem/progenitor cells were also enhanced and presented functional and transcriptomic alterations. Nonetheless, U2af1^mut/+Tet2^−/− mice did not succumb to MDS disease over a 6-month observation period. Collectively, our data suggest that cooperation between mutant U2af1 and Tet2 loss is not sufficient for MDS initiation in mice. Full article

(This article belongs to the Special Issue Hematological Malignancies)

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Review

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19 pages, 1389 KiB

Open AccessReview

Targeting the Interplay between HDACs and DNA Damage Repair for Myeloma Therapy

by Maria Gkotzamanidou, Elisavet Terpou, Nikolaos Kentepozidis and Evangelos Terpos

Int. J. Mol. Sci. 2021, 22(19), 10406; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910406 - 27 Sep 2021

Cited by 7 | Viewed by 2252

Abstract

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells, and accounts for 10% of all hematologic malignancies and 1% of all cancers. MM is characterized by genomic instability which results from DNA damage with certain genomic rearrangements being prognostic factors for [...] Read more.

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells, and accounts for 10% of all hematologic malignancies and 1% of all cancers. MM is characterized by genomic instability which results from DNA damage with certain genomic rearrangements being prognostic factors for the disease and patients’ clinical response. Following genotoxic stress, the evolutionary conserved DNA damage response (DDR) is activated and, in turn, coordinates DNA repair with cell-cycle events. However, the process of carcinogenesis cannot be attributed only to the genetic alterations, but also involves epigenetic processes. Regulation of expression and activity of key players in DNA repair and checkpoint proteins are essential and mediated partly by posttranslational modifications (PTM), such as acetylation. Crosstalk between different PTMs is important for regulation of DNA repair pathways. Acetylation, which is mediated by acetyltransferases (HAT) and histone deacetylases (HDAC), not only affects gene expression through its modulation of histone tails but also has recently been implicated in regulating non-histone proteins. Currently, several HDAC inhibitors (HDACi) have been developed both in pre-clinical and clinical studies, with some of them exhibiting significant anti-MM activities. Due to reversibility of epigenetic changes during the evolutionary process of myeloma genesis, the potency of epigenetic therapies seems to be of great importance. The aim of the present paper is the summary of all data on the role of HDACi in DDR, the interference with each DNA repair mechanism and the therapeutic implications of HDACi in MM. Full article

(This article belongs to the Special Issue Hematological Malignancies)

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33 pages, 774 KiB

Open AccessReview

Gene Transcription as a Therapeutic Target in Leukemia

by Alvina I. Khamidullina, Ekaterina A. Varlamova, Nour Alhuda Hammoud, Margarita A. Yastrebova and Alexandra V. Bruter

Int. J. Mol. Sci. 2021, 22(14), 7340; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147340 - 08 Jul 2021

Cited by 1 | Viewed by 3257

Abstract

Blood malignancies often arise from undifferentiated hematopoietic stem cells or partially differentiated stem-like cells. A tight balance of multipotency and differentiation, cell division, and quiescence underlying normal hematopoiesis requires a special program governed by the transcriptional machinery. Acquisition of drug resistance by tumor [...] Read more.

Blood malignancies often arise from undifferentiated hematopoietic stem cells or partially differentiated stem-like cells. A tight balance of multipotency and differentiation, cell division, and quiescence underlying normal hematopoiesis requires a special program governed by the transcriptional machinery. Acquisition of drug resistance by tumor cells also involves reprogramming of their transcriptional landscape. Limiting tumor cell plasticity by disabling reprogramming of the gene transcription is a promising strategy for improvement of treatment outcomes. Herein, we review the molecular mechanisms of action of transcription-targeted drugs in hematological malignancies (largely in leukemia) with particular respect to the results of clinical trials. Full article

(This article belongs to the Special Issue Hematological Malignancies)

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19 pages, 2668 KiB

Open AccessReview

Genetic Predisposition to Myelodysplastic Syndromes: A Challenge for Adult Hematologists

by Elena Crisà, Paola Boggione, Maura Nicolosi, Abdurraouf Mokhtar Mahmoud, Wael Al Essa, Bassel Awikeh, Anna Aspesi, Annalisa Andorno, Renzo Boldorini, Irma Dianzani, Gianluca Gaidano and Andrea Patriarca

Int. J. Mol. Sci. 2021, 22(5), 2525; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052525 - 03 Mar 2021

Cited by 2 | Viewed by 3218

Abstract

Myelodysplastic syndromes (MDS) arising in the context of inherited bone marrow failure syndromes (IBMFS) differ in terms of prognosis and treatment strategy compared to MDS occurring in the adult population without an inherited genetic predisposition. The main molecular pathways affected in IBMFS involve [...] Read more.

Myelodysplastic syndromes (MDS) arising in the context of inherited bone marrow failure syndromes (IBMFS) differ in terms of prognosis and treatment strategy compared to MDS occurring in the adult population without an inherited genetic predisposition. The main molecular pathways affected in IBMFS involve telomere maintenance, DNA repair, biogenesis of ribosomes, control of proliferation and others. The increased knowledge on the genes involved in MDS pathogenesis and the wider availability of molecular diagnostic assessment have led to an improvement in the detection of IBMFS genetic predisposition in MDS patients. A punctual recognition of these disorders implies a strict surveillance of the patient in order to detect early signs of progression and promptly offer allogeneic hematopoietic stem cell transplantation, which is the only curative treatment. Moreover, identifying an inherited mutation allows the screening and counseling of family members and directs the choice of donors in case of need for transplantation. Here we provide an overview of the most recent data on MDS with genetic predisposition highlighting the main steps of the diagnostic and therapeutic management. In order to highlight the pitfalls of detecting IBMFS in adults, we report the case of a 27-year-old man affected by MDS with an underlying telomeropathy. Full article

(This article belongs to the Special Issue Hematological Malignancies)

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13 pages, 1111 KiB

Open AccessReview

Acute Promyelocytic Leukemia in Children: A Model of Precision Medicine and Chemotherapy-Free Therapy

by Carmelo Gurnari, Maria Teresa Voso, Katia Girardi, Angela Mastronuzzi and Luisa Strocchio

Int. J. Mol. Sci. 2021, 22(2), 642; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020642 - 11 Jan 2021

Cited by 12 | Viewed by 9719

Abstract

Acute promyelocytic leukemia (APL) represents a paradigm of precision medicine. Indeed, in the last decades, the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) completely revolutionized the therapeutic approach to this previously highly fatal disorder. This entirely chemotherapy-free treatment, which provided [...] Read more.

Acute promyelocytic leukemia (APL) represents a paradigm of precision medicine. Indeed, in the last decades, the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) completely revolutionized the therapeutic approach to this previously highly fatal disorder. This entirely chemotherapy-free treatment, which provided excellent survival rates, has been initially validated in adults and, recently, translated in the pediatric setting. This review summarizes currently available data on the use of ATRA and ATO combination in pediatric APL, providing a particular focus on peculiar issues and challenges, such as the occurrence of pseudotumor cerebri and death during induction (early death), as well as the advantage offered by the ATO/ATRA combination in sparing long-term sequelae. Full article

(This article belongs to the Special Issue Hematological Malignancies)

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23 pages, 823 KiB

Open AccessReview

TP53 in Myelodysplastic Syndromes: Recent Biological and Clinical Findings

by Cosimo Cumbo, Giuseppina Tota, Luisa Anelli, Antonella Zagaria, Giorgina Specchia and Francesco Albano

Int. J. Mol. Sci. 2020, 21(10), 3432; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103432 - 13 May 2020

Cited by 26 | Viewed by 4420

Abstract

TP53 dysregulation plays a pivotal role in the molecular pathogenesis of myelodysplastic syndromes (MDS), identifying a subgroup of patients with peculiar features. In this review we report the recent biological and clinical findings of TP53-mutated MDS, focusing on the molecular pathways activation [...] Read more.

TP53 dysregulation plays a pivotal role in the molecular pathogenesis of myelodysplastic syndromes (MDS), identifying a subgroup of patients with peculiar features. In this review we report the recent biological and clinical findings of TP53-mutated MDS, focusing on the molecular pathways activation and on its impact on the cellular physiology. In MDS, TP53 mutational status is deeply associated with del(5q) syndrome and its dysregulation impacts on cell cycle, DNA repair and apoptosis inducing chromosomal instability and the clonal evolution of disease. TP53 defects influence adversely the MDS clinical outcome and the treatment response rate, thus new therapeutic approaches are being developed for these patients. TP53 allelic state characterization and the mutational burden evaluation can therefore predict prognosis and identify the subgroup of patients eligible for targeted therapy. For these reasons, in the era of precision medicine, the MDS diagnostic workup cannot do without the complete assessment of TP53 mutational profile. Full article

(This article belongs to the Special Issue Hematological Malignancies)

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