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Molecular Cell Jun 2021Riedel et al. (2021) show that expression of MN1 is capable of blocking myeloid differentiation and initiating leukemia through mechanisms that require Brg1-containing...
Riedel et al. (2021) show that expression of MN1 is capable of blocking myeloid differentiation and initiating leukemia through mechanisms that require Brg1-containing chromatin remodeling complexes. Intriguingly, this process depends on an unstructured polyglutamine repeat region within MN1.
Topics: Humans; Leukemia, Myeloid, Acute; Meningeal Neoplasms; Meningioma; Trans-Activators; Tumor Suppressor Proteins
PubMed: 34087176
DOI: 10.1016/j.molcel.2021.05.001 -
Scientific Reports Dec 2021Central nervous system (CNS) relapse is a significant cause of treatment failure among patients with acute lymphoblastic leukemia. In prior work we found that the...
Central nervous system (CNS) relapse is a significant cause of treatment failure among patients with acute lymphoblastic leukemia. In prior work we found that the meninges, the thin layer of tissue that covers the brain and spinal cord, harbor leukemia cells in the CNS. Importantly, direct interactions between leukemia and meningeal cells enabled leukemia chemoresistance. Herein, we show that an antibody targeting CD99, a transmembrane protein expressed on meningeal cells and many leukemia cells, disrupts adhesion between leukemia and meningeal cells and restores sensitivity of the leukemia cells to chemotherapy. This work identifies a mechanism regulating critical intercellular interactions within the CNS leukemia niche and may lead to novel therapeutic approaches for overcoming niche-mediated chemoresistance.
Topics: 12E7 Antigen; Antibodies, Monoclonal; Drug Resistance, Neoplasm; Humans; Meningeal Neoplasms; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured
PubMed: 34934147
DOI: 10.1038/s41598-021-03929-x -
Frontiers in Cell and Developmental... 2021Involvement of the Central Nervous System (CNS) in acute leukemia confers poor prognosis and lower overall survival. Existing CNS-directed therapies are associated with... (Review)
Review
Involvement of the Central Nervous System (CNS) in acute leukemia confers poor prognosis and lower overall survival. Existing CNS-directed therapies are associated with a significant risk of short- or long-term toxicities. Leukemic cells can metabolically adapt and survive in the microenvironment of the CNS. The supporting role of the CNS microenvironment in leukemia progression and dissemination has not received sufficient attention. Understanding the mechanism by which leukemic cells survive in the nutrient-poor and oxygen-deprived CNS microenvironment will lead to the development of more specific and less toxic therapies. Here, we review the current literature regarding the roles of metabolic reprogramming in leukemic cell adhesion and survival in the CNS.
PubMed: 34957100
DOI: 10.3389/fcell.2021.767510 -
British Journal of Haematology May 2023The effective prophylaxis and treatment of central nervous system (CNS) involvement in acute lymphoblastic leukaemia (ALL) remains a significant clinical challenge....
The effective prophylaxis and treatment of central nervous system (CNS) involvement in acute lymphoblastic leukaemia (ALL) remains a significant clinical challenge. Developing novel and more effective CNS-directed therapies has been hampered, in part, by our limited understanding of the leukaemia niche in the CNS relative to the bone marrow. Accordingly, defining the molecular and cellular components critical for the establishment and maintenance of the CNS leukaemia niche may lead to new therapeutic opportunities. In prior work we showed that direct intercellular interactions between leukaemia and meningeal cells enhance leukaemia chemoresistance in the CNS. Herein, we show that the CXCR4/CXCL12 chemokine axis contributes to leukaemia-meningeal cell adhesion. Importantly, clinically tested CXCR4 antagonists, which are likely to cross the blood-brain and blood-cerebral spinal fluid barriers and penetrate the CNS, effectively disrupted leukaemia-meningeal cell adhesion. Moreover, by disrupting these intercellular interactions, CXCR4 antagonists attenuated leukaemia chemoresistance in leukaemia-meningeal cell co-culture experiments and enhanced the efficacy of cytarabine in targeting leukaemia cells in the meninges in vivo. This work identifies the CXCR4/CXCL12 axis as an important regulator of intercellular interactions within the CNS leukaemia niche and supports further testing of the therapeutic efficacy of CXCR4 antagonists in overcoming CNS niche-mediated chemoresistance.
Topics: Humans; Cell Adhesion; Drug Resistance, Neoplasm; Leukemia; Signal Transduction; Receptors, CXCR4; Chemokine CXCL12; Meninges
PubMed: 36535585
DOI: 10.1111/bjh.18607 -
Cancers Feb 2021Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic... (Review)
Review
Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Ara-C-based chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. Several studies suggest that the individual variability in clinical response to Leukemia & Lymphoma treatments among patients, underlying either Ara-C mechanism resistance or toxicity, appears to be associated with the intracellular accumulation and retention of Ara-CTP due to genetic variants related to metabolic enzymes. Herein, we reported (a) the latest Pharmacogenomics biomarkers associated with the response to cytarabine and (b) the new drug formulations with optimized pharmacokinetics. The purpose of this review is to provide readers with detailed and comprehensive information on the effects of Ara-C-based therapies, from biological to clinical practice, maintaining high the interest of both researcher and clinical hematologist. This review could help clinicians in predicting the response to cytarabine-based treatments.
PubMed: 33669053
DOI: 10.3390/cancers13050966 -
Seminars in Ultrasound, CT, and MR Feb 2022The central nervous system (CNS) tumors constitute the most common type of solid tumors in the pediatric population. The cerebral and cerebellar parenchyma are the most... (Review)
Review
The central nervous system (CNS) tumors constitute the most common type of solid tumors in the pediatric population. The cerebral and cerebellar parenchyma are the most common site of pediatric CNS neoplasms. Imaging plays an important role in detection, characterization, staging and prognostication of brain tumors. The focus of the current article is pediatric brain tumor imaging with emphasis on pearls and pitfalls of conventional and advanced imaging in various pediatric brain tumor subtypes. The article also elucidates changes in brain tumor terms and entities as applicable to pediatric patients, updated as per World Health Organization (WHO) 2016 classification of primary CNS tumors. This classification introduced the genetic and/or molecular information of primary CNS neoplasms as part of comprehensive tumor pathology report in the routine clinical workflow. The concepts from 2016 classification have been further refined based on current research, by the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) group and published in the form of updates. The updates serve as guidelines in the time interval between WHO updates and expect to be broadly adopted in the subsequent WHO classification. The current review covers most pediatric brain tumors except pituitary tumors, meningeal origin tumors, nerve sheath tumors and CNS lymphoma/leukemia.
Topics: Brain Neoplasms; Central Nervous System Neoplasms; Child; Diagnostic Imaging; Humans; World Health Organization
PubMed: 35164908
DOI: 10.1053/j.sult.2021.05.004 -
Future Microbiology Dec 2019Cryptococcosis causes significant morbidity and mortality worldwide, but pediatric data are limited. A retrospective literature review of Australian pediatric... (Review)
Review
Cryptococcosis causes significant morbidity and mortality worldwide, but pediatric data are limited. A retrospective literature review of Australian pediatric cryptococcosis and additional 10-year audit of cases from a large pediatric network. 22 cases of cryptococcosis in children were identified via literature review: median age was 13.5 years (IQR 7.8-16 years), 18/22 (82%) had meningitis or central nervous system infection. Where outcome was reported, 11/18 (61%) died. Of six audit cases identified from 2008 to 2017, 5 (83%) had disease and survived. One child with acute lymphoblastic leukemia and infection died. For survivors, persisting respiratory or neurological sequelae were reported in 4/6 cases (67%). Cryptococcosis is uncommon in Australian children, but is associated with substantial morbidity.
Topics: Adolescent; Australia; Child; Cryptococcosis; Cryptococcus gattii; Cryptococcus neoformans; Female; Humans; Male; Meningitis, Cryptococcal; Retrospective Studies
PubMed: 31992070
DOI: 10.2217/fmb-2019-0215 -
Pediatric Neurosurgery 2022Following cranial irradiation, there is an increased risk of developing secondary neoplasms, especially meningiomas. Despite childhood cancer survivors who have... (Review)
Review
INTRODUCTION
Following cranial irradiation, there is an increased risk of developing secondary neoplasms, especially meningiomas. Despite childhood cancer survivors who have undergone cranial irradiation having an increased risk of acquiring radiation-induced meningioma (RIM), there is no widely used standard guideline for meningioma screening.
METHODS
At a single institution, we reviewed three adult survivors of childhood cancer who were treated for RIM between 2010 and 2020. We recorded age at diagnosis for the primary lesion, the radiation dose, age at RIM diagnosis, and tumor characteristics including treatment, pathology, and outcome. Two had had T-cell acute lymphocytic leukemia and one a rhabdomyosarcoma. The age of diagnosis of the RIM ranged from 20 to 40 years, with latencies ranging from 18 to 33 years. All lesions were classified as WHO Grade I meningiomas, and only 1 patient had a subsequent recurrence. A literature search identified articles that address RIM: a total of 684 cases were identified in 36 publications.
RESULTS
Mean radiation doses ranged from 1.4 gray to 70 gray. Mean age of diagnosis for secondary meningioma ranged from 8 to 53.4 years old, with latency periods ranging from 2.8 to 44 years. Given variability in the way that investigators have published their results, it is difficult to make a single recommendation for RIM screening. Using our experience and the literature, we devised two different screening protocols and calculated their expense.
CONCLUSIONS
We recommend that data be standardized in a registry to provide greater insight into the clinical and resource allocation questions, especially as long-term survival of children with pediatric cancer into full adulthood becomes more commonplace worldwide.
Topics: Child; Adult; Humans; Adolescent; Young Adult; Middle Aged; Meningioma; Neoplasms, Radiation-Induced; Cranial Irradiation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Meningeal Neoplasms
PubMed: 36252549
DOI: 10.1159/000527565 -
Haematologica Aug 2020Protection from acute lymphoblastic leukemia relapse in the central nervous system (CNS) is crucial to survival and quality of life for leukemia patients. Current...
Protection from acute lymphoblastic leukemia relapse in the central nervous system (CNS) is crucial to survival and quality of life for leukemia patients. Current CNS-directed therapies cause significant toxicities and are only partially effective. Moreover, the impact of the CNS microenvironment on leukemia biology is poorly understood. In this study we showed that leukemia cells associated with the meninges of xenotransplanted mice, or co-cultured with meningeal cells, exhibit enhanced chemoresistance due to effects on both apoptosis balance and quiescence. From a mechanistic standpoint, we found that leukemia chemoresistance is primarily mediated by direct leukemia-meningeal cell interactions and overcome by detaching the leukemia cells from the meninges. Next, we used a co-culture adhesion assay to identify drugs that disrupted leukemia-meningeal adhesion. In addition to identifying several drugs that inhibit canonical cell adhesion targets we found that Me6TREN (Tris[2-(dimethylamino)ethyl]amine), a novel hematopoietic stem cell-mobilizing compound, also disrupted leukemia-meningeal adhesion and enhanced the efficacy of cytarabine in treating CNS leukemia in xenotransplanted mice. This work demonstrates that the meninges exert a critical influence on leukemia chemoresistance, elucidates mechanisms of relapse beyond the well-described role of the blood-brain barrier, and identifies novel therapeutic approaches for overcoming chemoresistance.
Topics: Animals; Central Nervous System; Cytarabine; Drug Resistance, Neoplasm; Humans; Leukemia; Mice; Quality of Life; Tumor Microenvironment
PubMed: 31624109
DOI: 10.3324/haematol.2019.230334 -
Central nervous system manifestations of systemic haematological malignancies and key differentials.Clinical Radiology May 2022Central nervous system (CNS) involvement by haematological malignancies is uncommon, and generally associated with a poor prognosis. Neuroimaging plays a key role in the... (Review)
Review
Central nervous system (CNS) involvement by haematological malignancies is uncommon, and generally associated with a poor prognosis. Neuroimaging plays a key role in the accurate diagnosis, including in the critical differentiation from other processes such as infection and treatment-related toxicity. This review illustrates a variety of manifestations of CNS involvement by haematological malignancies and relevant differential diagnoses. CNS involvement can be seen in lymphoma (both primary and secondary), Waldenström macroglobulinaemia, multiple myeloma, leukaemia, and the malignant histiocytoses. The typical patterns vary between the different disorders, for example, in the most common sites of involvement and the relative frequency of parenchymal and meningeal involvement. Adjacent structures may also be involved. Nevertheless, there is some overlap in the imaging appearances, with common features including pre-contrast hyperdensity on computed tomography (CT), diffusion restriction, and avid post-contrast enhancement. In the post-treatment context, it is also important to distinguish between disease relapse and post-treatment effects. This includes opportunistic infections and the effects of chemotherapy and/or radiotherapy, including toxic effects and radiotherapy-induced neoplasms.
Topics: Central Nervous System; Central Nervous System Neoplasms; Hematologic Neoplasms; Humans; Lymphoma; Neuroimaging; Tomography, X-Ray Computed
PubMed: 35164931
DOI: 10.1016/j.crad.2022.01.043