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Cancers
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Childhood Leukemia
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Childhood Leukemia

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 47123

Special Issue Editors

Dr. Sinisa Dovat

E-Mail Website1 Website2
Guest Editor
Penn State College of Medicine, Hershey, United States
Interests: childhood leukemia; hematological malignancies; transcriptional regulation; gene expression; epigenetics; signal transduction; tumor suppression; targeted therapy; acute lymphoblastic leukemia; combination therapies
Dr. Karmen Stankov

E-Mail Website
Guest Editor
Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
Interests: translational cancer research; pharmacogenomics; cancer genetics; medical biochemistry; clinical pharmacology; clinical genetics; diabetes genetics; nanomedicine; bile acid research; oxidative medicine

Special Issue Information

Dear Colleagues,

Childhood leukemia is the most common malignancy in children. It encompasses several types of hematological malignancy, each with unique pathogeneses and treatment strategies. Over the past 70 years, we have witnessed tremendous progress towards understanding the mechanisms of leukemogenesis and developing novel treatments for these diseases.

The discovery of tumor suppressors, as well as oncogenes that act as major drivers of malignant transformation, provided insights into the transcriptional network and signaling pathways that regulate gene expression in leukemia. The use of next-generation sequencing furthered our understanding of the molecular mechanisms of malignant transformation and relapse, discovery of novel biomarkers, and ultimately to the development of a molecular classification of leukemia, with the identification of novel subtypes of high-risk leukemia (e.g., Ph-like B-cell acute lymphoblastic leukemia).

Clinical research led by clinical trial groups resulted in advanced therapeutic protocols. The development of targeted therapy as well as immunotherapy with chimeric antigen receptor T cells (CAR-T cell therapy) paved the way to a precision medicine approach. Advances in stem cell transplant protocols and techniques led to an improved outcome following this procedure. The above-described research advances improved the treatment and overall prognosis of childhood leukemia, resulting in a current 5-year survival rate of 83.6% for pediatric leukemia, as compared to less than 37% survival in 1975.

There are currently challenges associated with elucidating the basic mechanisms of the malignant transformation, progression, and development of chemotherapy resistance in childhood leukemia. Clinically, further improvement of overall survival, understanding the long-term effects of chemotherapy, reducing racial health disparities in childhood leukemia, and advancing immunotherapy and stem cell transplantation are only some of the current challenges in this field.

This Special Issue will highlight the basic, translational, and clinical aspects of childhood leukemia, along with the latest advances and future directions in understanding molecular mechanisms of pathogenesis, clinical presentation, and treatment of these diseases.

Dr. Sinisa Dovat
Dr. Karmen Stankov
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 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.

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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • leukemia
  • pediatrics
  • novel therapy
  • pathogenesis
  • gene expression
  • signal transduction
  • precision medicine
  • epigenetics
  • oncogene
  • tumor suppression

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Published Papers (9 papers)

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Research

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20 pages, 3528 KiB  
Article
Elucidating the Importance of DOT1L Recruitment in MLL-AF9 Leukemia and Hematopoiesis
by Sierrah M. Grigsby, Ann Friedman, Jennifer Chase, Bridget Waas, James Ropa, Justin Serio, Chenxi Shen, Andrew G. Muntean, Ivan Maillard and Zaneta Nikolovska-Coleska
Cancers 2021, 13(4), 642; https://doi.org/10.3390/cancers13040642 - 5 Feb 2021
Cited by 12 | Viewed by 4462
Abstract
MLL1 (KMT2a) gene rearrangements underlie the pathogenesis of aggressive MLL-driven acute leukemia. AF9, one of the most common MLL-fusion partners, recruits the histone H3K79 methyltransferase DOT1L to MLL target genes, constitutively activating transcription of pro-leukemic targets. DOT1L has emerged as a therapeutic target [...] Read more.
MLL1 (KMT2a) gene rearrangements underlie the pathogenesis of aggressive MLL-driven acute leukemia. AF9, one of the most common MLL-fusion partners, recruits the histone H3K79 methyltransferase DOT1L to MLL target genes, constitutively activating transcription of pro-leukemic targets. DOT1L has emerged as a therapeutic target in patients with MLL-driven leukemia. However, global DOT1L enzymatic inhibition may lead to off-target toxicities in non-leukemic cells that could decrease the therapeutic index of DOT1L inhibitors. To bypass this problem, we developed a novel approach targeting specific protein-protein interactions (PPIs) that mediate DOT1L recruitment to MLL target genes, and compared the effects of enzymatic and PPIs inhibition on leukemic and non-leukemic hematopoiesis. MLL-AF9 cell lines were engineered to carry mutant DOT1L constructs with a defective AF9 interaction site or lacking enzymatic activity. In cell lines expressing a DOT1L mutant with defective AF9 binding, we observed complete disruption of DOT1L recruitment to critical target genes and inhibition of leukemic cell growth. To evaluate the overall impact of DOT1L loss in non-leukemic hematopoiesis, we first assessed the impact of acute Dot1l inactivation in adult mouse bone marrow. We observed a rapid reduction in myeloid progenitor cell numbers within 7 days, followed by a loss of long-term hematopoietic stem cells. Furthermore, WT and PPI-deficient DOT1L mutants but not an enzymatically inactive DOT1L mutant were able to rescue sustained hematopoiesis. These data show that the AF9-DOT1L interaction is dispensable in non-leukemic hematopoiesis. Our findings support targeting of the MLL-AF9–DOT1L interaction as a promising therapeutic strategy that is selectively toxic to MLL-driven leukemic cells. Full article
(This article belongs to the Special Issue Childhood Leukemia)
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18 pages, 4535 KiB  
Article
Inhibition of Methyltransferase DOT1L Sensitizes to Sorafenib Treatment AML Cells Irrespective of MLL-Rearrangements: A Novel Therapeutic Strategy for Pediatric AML
by Annalisa Lonetti, Valentina Indio, Maria Antonella Laginestra, Giuseppe Tarantino, Francesca Chiarini, Annalisa Astolfi, Salvatore N. Bertuccio, Alberto M. Martelli, Franco Locatelli, Andrea Pession and Riccardo Masetti
Cancers 2020, 12(7), 1972; https://doi.org/10.3390/cancers12071972 - 20 Jul 2020
Cited by 21 | Viewed by 3811
Abstract
Pediatric acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis for which there are few effective targeted approaches, despite the numerous genetic alterations, including MLL gene rearrangements (MLL-r). The histone methyltransferase DOT1L is involved in supporting the proliferation of [...] Read more.
Pediatric acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis for which there are few effective targeted approaches, despite the numerous genetic alterations, including MLL gene rearrangements (MLL-r). The histone methyltransferase DOT1L is involved in supporting the proliferation of MLL-r cells, for which a target inhibitor, Pinometostat, has been evaluated in a clinical trial recruiting pediatric MLL-r leukemic patients. However, modest clinical effects have been observed. Recent studies have reported that additional leukemia subtypes lacking MLL-r are sensitive to DOT1L inhibition. Here, we report that targeting DOT1L with Pinometostat sensitizes pediatric AML cells to further treatment with the multi-kinase inhibitor Sorafenib, irrespectively of MLL-r. DOT1L pharmacologic inhibition induces AML cell differentiation and modulates the expression of genes with relevant roles in cancer development. Such modifications in the transcriptional program increase the apoptosis and growth suppression of both AML cell lines and primary pediatric AML cells with diverse genotypes. Through ChIP-seq analysis, we identified the genes regulated by DOT1L irrespective of MLL-r, including the Sorafenib target BRAF, providing mechanistic insights into the drug combination activity. Our results highlight a novel therapeutic strategy for pediatric AML patients. Full article
(This article belongs to the Special Issue Childhood Leukemia)
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19 pages, 3870 KiB  
Article
Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support
by Yasser Perera, Alice Melão, Ailyn C. Ramón, Dania Vázquez, Daniel Ribeiro, Silvio E. Perea and João T. Barata
Cancers 2020, 12(6), 1377; https://doi.org/10.3390/cancers12061377 - 27 May 2020
Cited by 12 | Viewed by 3655
Abstract
Despite remarkable advances in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), relapsed cases are still a major challenge. Moreover, even successful cases often face long-term treatment-associated toxicities. Targeted therapeutics may overcome these limitations. We have previously demonstrated that casein kinase 2 (CK2)-mediated [...] Read more.
Despite remarkable advances in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), relapsed cases are still a major challenge. Moreover, even successful cases often face long-term treatment-associated toxicities. Targeted therapeutics may overcome these limitations. We have previously demonstrated that casein kinase 2 (CK2)-mediated phosphatase and tensin homologue (PTEN) posttranslational inactivation, and consequent phosphatidylinositol 3-kinase (PI3K)/Akt signaling hyperactivation, leads to increased T-ALL cell survival and proliferation. We also revealed the existence of a crosstalk between CK2 activity and the signaling mediated by interleukin 7 (IL-7), a critical leukemia-supportive cytokine. Here, we evaluated the impact of CIGB-300, a the clinical-grade peptide-based CK2 inhibitor CIGB-300 on T-ALL biology. We demonstrate that CIGB-300 decreases the viability and proliferation of T-ALL cell lines and diagnostic patient samples. Moreover, CIGB-300 overcomes IL-7-mediated T-ALL cell growth and viability, while preventing the positive effects of OP9-delta-like 1 (DL1) stromal support on leukemia cells. Signaling and pull-down experiments indicate that the CK2 substrate nucleophosmin 1 (B23/NPM1) and CK2 itself are the molecular targets for CIGB-300 in T-ALL cells. However, B23/NPM1 silencing only partially recapitulates the anti-leukemia effects of the peptide, suggesting that CIGB-300-mediated direct binding to CK2, and consequent CK2 inactivation, is the mechanism by which CIGB-300 downregulates PTEN S380 phosphorylation and inhibits PI3K/Akt signaling pathway. In the context of IL-7 stimulation, CIGB-300 blocks janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in T-ALL cells. Altogether, our results strengthen the case for anti-CK2 therapeutic intervention in T-ALL, demonstrating that CIGB-300 (given its ability to circumvent the effects of pro-leukemic microenvironmental cues) may be a valid tool for clinical intervention in this aggressive malignancy. Full article
(This article belongs to the Special Issue Childhood Leukemia)
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27 pages, 7489 KiB  
Article
Glucocorticoid Resistant Pediatric Acute Lymphoblastic Leukemia Samples Display Altered Splicing Profile and Vulnerability to Spliceosome Modulation
by Rocco Sciarrillo, Anna Wojtuszkiewicz, Irsan E. Kooi, Leticia G. Leon, Edwin Sonneveld, Roland P. Kuiper, Gerrit Jansen, Elisa Giovannetti, Gertjan J.L. Kaspers and Jacqueline Cloos
Cancers 2020, 12(3), 723; https://doi.org/10.3390/cancers12030723 - 19 Mar 2020
Cited by 16 | Viewed by 4216
Abstract
Glucocorticoid (GC) resistance is a crucial determinant of inferior response to chemotherapy in pediatric acute lymphoblastic leukemia (ALL); however, molecular mechanisms underlying this phenomenon are poorly understood. Deregulated splicing is a common feature of many cancers, which impacts drug response and constitutes an [...] Read more.
Glucocorticoid (GC) resistance is a crucial determinant of inferior response to chemotherapy in pediatric acute lymphoblastic leukemia (ALL); however, molecular mechanisms underlying this phenomenon are poorly understood. Deregulated splicing is a common feature of many cancers, which impacts drug response and constitutes an attractive therapeutic target. Therefore, the aim of the current study was to characterize global splicing profiles associated with GC resistance and determine whether splicing modulation could serve as a novel therapeutic option for GC-resistant patients. To this end, 38 primary ALL samples were profiled using RNA-seq-based differential splicing analysis. The impact of splicing modulators was investigated in GC-resistant leukemia cell lines and primary leukemic specimens. Our findings revealed, for the first time, markedly distinct splicing landscapes in ALL samples of B-cell precursor (BCP)-ALL and T-ALL lineages. Differential splicing events associated with GC resistance were involved in RNA processing, a direct response to GCs, survival signaling, apoptosis, cell cycle regulation and energy metabolism. Furthermore, our analyses showed that GC-resistant ALL cell lines and primary samples are sensitive to splicing modulation, alone and in combination with GC. Together, these findings suggest that aberrant splicing is associated with GC resistance and splicing modulators deserve further interest as a novel treatment option for GC-resistant patients. Full article
(This article belongs to the Special Issue Childhood Leukemia)
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Review

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18 pages, 1432 KiB  
Review
Cerebrospinal Fluid Biomarkers in Childhood Leukemias
by Chrysanthy Ikonomidou
Cancers 2021, 13(3), 438; https://doi.org/10.3390/cancers13030438 - 24 Jan 2021
Cited by 5 | Viewed by 3541
Abstract
Involvement of the central nervous system (CNS) in childhood leukemias remains a major cause of treatment failures. Analysis of the cerebrospinal fluid constitutes the most important diagnostic pillar in the detection of CNS leukemia and relies primarily on cytological and flow-cytometry studies. With [...] Read more.
Involvement of the central nervous system (CNS) in childhood leukemias remains a major cause of treatment failures. Analysis of the cerebrospinal fluid constitutes the most important diagnostic pillar in the detection of CNS leukemia and relies primarily on cytological and flow-cytometry studies. With increasing survival rates, it has become clear that treatments for pediatric leukemias pose a toll on the developing brain, as they may cause acute toxicities and persistent neurocognitive deficits. Preclinical research has demonstrated that established and newer therapies can injure and even destroy neuronal and glial cells in the brain. Both passive and active cell death forms can result from DNA damage, oxidative stress, cytokine release, and acceleration of cell aging. In addition, chemotherapy agents may impair neurogenesis as well as the function, formation, and plasticity of synapses. Clinical studies show that neurocognitive toxicity of chemotherapy is greatest in younger children. This raises concerns that, in addition to injury, chemotherapy may also disrupt crucial developmental events resulting in impairment of the formation and efficiency of neuronal networks. This review presents an overview of studies demonstrating that cerebrospinal fluid biomarkers can be utilized in tracing both CNS disease and neurotoxicity of administered treatments in childhood leukemias. Full article
(This article belongs to the Special Issue Childhood Leukemia)
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30 pages, 672 KiB  
Review
The Role of cis- and trans-Acting RNA Regulatory Elements in Leukemia
by Irina A. Elcheva and Vladimir S. Spiegelman
Cancers 2020, 12(12), 3854; https://doi.org/10.3390/cancers12123854 - 20 Dec 2020
Cited by 18 | Viewed by 5372
Abstract
RNA molecules are a source of phenotypic diversity and an operating system that connects multiple genetic and metabolic processes in the cell. A dysregulated RNA network is a common feature of cancer. Aberrant expression of long non-coding RNA (lncRNA), micro RNA (miRNA), and [...] Read more.
RNA molecules are a source of phenotypic diversity and an operating system that connects multiple genetic and metabolic processes in the cell. A dysregulated RNA network is a common feature of cancer. Aberrant expression of long non-coding RNA (lncRNA), micro RNA (miRNA), and circular RNA (circRNA) in tumors compared to their normal counterparts, as well as the recurrent mutations in functional regulatory cis-acting RNA motifs have emerged as biomarkers of disease development and progression, opening avenues for the design of novel therapeutic approaches. This review looks at the progress, challenges and future prospects of targeting cis-acting and trans-acting RNA elements for leukemia diagnosis and treatment. Full article
(This article belongs to the Special Issue Childhood Leukemia)
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13 pages, 252 KiB  
Review
Pain Management in Childhood Leukemia: Diagnosis and Available Analgesic Treatments
by Flaminia Coluzzi, Monica Rocco, Rula Green Gladden, Pietro Persiani, Laurel A. Thur and Filippo Milano
Cancers 2020, 12(12), 3671; https://doi.org/10.3390/cancers12123671 - 7 Dec 2020
Cited by 13 | Viewed by 4608
Abstract
Pain is one of the most common symptoms in children suffering from leukemia, who are often misdiagnosed with other childhood painful diseases such as juvenile idiopathic arthritis. Corticosteroid-induced osteonecrosis (ON) and vincristine-induced peripheral neuropathy (VIPN) are the most common painful manifestations. Additionally, ongoing [...] Read more.
Pain is one of the most common symptoms in children suffering from leukemia, who are often misdiagnosed with other childhood painful diseases such as juvenile idiopathic arthritis. Corticosteroid-induced osteonecrosis (ON) and vincristine-induced peripheral neuropathy (VIPN) are the most common painful manifestations. Additionally, ongoing pain may continue to impact quality of life in survivorship. This narrative review focuses on the pathophysiological mechanisms of pain in childhood leukemia and current available indications for analgesic treatments. Pain management in children is often inadequate because of difficulties in pain assessment, different indications across countries, and the lack of specific pediatric trials. Analgesic drugs are often prescribed off-label to children by extrapolating information from adult guidelines, with possible increased risk of adverse events. Optimal pain management should involve a multidisciplinary team to ensure assessment and interventions tailored to the individual patient. Full article
(This article belongs to the Special Issue Childhood Leukemia)
27 pages, 933 KiB  
Review
B-ALL Complexity: Is Targeted Therapy Still A Valuable Approach for Pediatric Patients?
by Stefano Ratti, Annalisa Lonetti, Matilde Y. Follo, Francesca Paganelli, Alberto M. Martelli, Francesca Chiarini and Camilla Evangelisti
Cancers 2020, 12(12), 3498; https://doi.org/10.3390/cancers12123498 - 24 Nov 2020
Cited by 14 | Viewed by 4250
Abstract
B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy that arises from the clonal expansion of transformed B-cell precursors and predominately affects childhood. Even though significant progresses have been made in the treatment of B-ALL, pediatric patients’ outcome has to be furtherly increased [...] Read more.
B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy that arises from the clonal expansion of transformed B-cell precursors and predominately affects childhood. Even though significant progresses have been made in the treatment of B-ALL, pediatric patients’ outcome has to be furtherly increased and alternative targeted treatment strategies are required for younger patients. Over the last decade, novel approaches have been used to understand the genomic landscape and the complexity of the molecular biology of pediatric B-ALL, mainly next generation sequencing, offering important insights into new B-ALL subtypes, altered pathways, and therapeutic targets that may lead to improved risk stratification and treatments. Here, we will highlight the up-to-date knowledge of the novel B-ALL subtypes in childhood, with particular emphasis on altered signaling pathways. In addition, we will discuss the targeted therapies that showed promising results for the treatment of the different B-ALL subtypes. Full article
(This article belongs to the Special Issue Childhood Leukemia)
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17 pages, 678 KiB  
Review
Repurposing Drugs for Acute Myeloid Leukemia: A Worthy Cause or a Futile Pursuit?
by Anna V. Wojcicki, Meena Kadapakkam, Adam Frymoyer, Norman Lacayo, Hee-Don Chae and Kathleen M. Sakamoto
Cancers 2020, 12(2), 441; https://doi.org/10.3390/cancers12020441 - 13 Feb 2020
Cited by 17 | Viewed by 11878
Abstract
Acute myeloid leukemia (AML) is a clinically and genetically heterogenous malignancy of myeloid progenitor cells that affects patients of all ages. Despite decades of research and improvement in overall outcomes, standard therapy remains ineffective for certain subtypes of AML. Current treatment is intensive [...] Read more.
Acute myeloid leukemia (AML) is a clinically and genetically heterogenous malignancy of myeloid progenitor cells that affects patients of all ages. Despite decades of research and improvement in overall outcomes, standard therapy remains ineffective for certain subtypes of AML. Current treatment is intensive and leads to a number of secondary effects with varying results by patient population. Due to the high cost of discovery and an unmet need for new targeted therapies that are well tolerated, alternative drug development strategies have become increasingly attractive. Repurposing existing drugs is one approach to identify new therapies with fewer financial and regulatory hurdles. In this review, we provide an overview of previously U.S. Food and Drug Administration (FDA) approved non-chemotherapy drugs under investigation for the treatment of AML. Full article
(This article belongs to the Special Issue Childhood Leukemia)
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