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International Journal of Molecular... Feb 2022Self-maintaining hematopoietic stem cells are a cell population that is primarily 'at risk' to malignant transformation, and the cell-of-origin for some leukemias.... (Review)
Review
Self-maintaining hematopoietic stem cells are a cell population that is primarily 'at risk' to malignant transformation, and the cell-of-origin for some leukemias. Tissue-specific stem cells replenish the different types of functional cells within a particular tissue to meet the demands of an organism. For hematopoietic stem cells, this flexibility is important to satisfy the changing requirements for a certain type of immune cell, when needed. From studies of the natural history of childhood acute lymphoblastic leukemia, an initial oncogenic and prenatal insult gives rise to a preleukemic clone. At least a second genomic insult is needed that gives rise to a leukemia stem cell: this cell generates a hierarchy of leukemia cells. For some leukemias, there is evidence to support the concept that one of the genomic insults leads to dysregulation of the tissue homeostatic role of hematopoietic stem cells so that the hierarchy of differentiating leukemia cells belongs to just one cell lineage. Restricting the expression of particular oncogenes in transgenic mice to hematopoietic stem and progenitor cells led to different human-like lineage-restricted leukemias. Lineage restriction is seen for human leukemias by virtue of their sub-grouping with regard to a phenotypic relationship to just one cell lineage.
Topics: Animals; Cell Transformation, Neoplastic; Hematopoietic Stem Cells; Humans; Leukemia; Oncogenes
PubMed: 35216407
DOI: 10.3390/ijms23042293 -
Frontiers in Public Health 2021
Topics: Acute Disease; Child; Humans; Leukemia
PubMed: 34434914
DOI: 10.3389/fpubh.2021.700739 -
Leukemia Sep 2020The bone marrow is home to well-balanced normal hematopoiesis, but also the stage of leukemia's crime. Marrow adipose tissue (MAT) is a unique and versatile component of... (Review)
Review
The bone marrow is home to well-balanced normal hematopoiesis, but also the stage of leukemia's crime. Marrow adipose tissue (MAT) is a unique and versatile component of the bone marrow niche. While the importance of MAT for bone health has long been recognized, its complex role in hematopoiesis has only recently gained attention. In this review article we summarize recent conceptual advances in the field of MAT research and how these developments impact our understanding of MAT regulation of hematopoiesis. Elucidating routes of interaction and regulation between MAT and cells of the hematopoietic system are essential to pinpoint vulnerable processes resulting in malignant transformation. The concept of white adipose tissue contributing to cancer development and progression on the cellular, metabolic, and systemic level is generally accepted. The role of MAT in malignant hematopoiesis, however, is controversial. MAT is very sensitive to changes in the patient's metabolic status hampering a clear definition of its role in different clinical situations. Here, we discuss future directions for leukemia research in the context of metabolism-induced modifications of MAT and other adipose tissues and how this might impact on leukemia cell survival, proliferation, and antileukemic therapy.
Topics: Acute Disease; Adipocytes; Animals; Hematopoiesis; Humans; Leukemia; Tumor Microenvironment
PubMed: 32474572
DOI: 10.1038/s41375-020-0886-x -
International Journal of Molecular... Jun 2021In recent decades, the conduct of uniform prospective clinical trials has led to improved remission rates and survival for patients with acute myeloid leukaemia and... (Review)
Review
In recent decades, the conduct of uniform prospective clinical trials has led to improved remission rates and survival for patients with acute myeloid leukaemia and acute lymphoblastic leukaemia. However, high-risk patients continue to have inferior outcomes, where chemoresistance and relapse are common due to the survival mechanisms utilised by leukaemic cells. One such mechanism is through hijacking of the bone marrow microenvironment, where healthy haematopoietic machinery is transformed or remodelled into a hiding ground or "sanctuary" where leukaemic cells can escape chemotherapy-induced cytotoxicity. The bone marrow microenvironment, which consists of endosteal and vascular niches, can support leukaemogenesis through intercellular "crosstalk" with niche cells, including mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts. Here, we summarise the regulatory mechanisms associated with leukaemia-bone marrow niche interaction and provide a comprehensive review of the key therapeutics that target CXCL12/CXCR4, Notch, Wnt/b-catenin, and hypoxia-related signalling pathways within the leukaemic niches and agents involved in remodelling of niche bone and vasculature. From a therapeutic perspective, targeting these cellular interactions is an exciting novel strategy for enhancing treatment efficacy, and further clinical application has significant potential to improve the outcome of patients with leukaemia.
Topics: Animals; Antineoplastic Agents; Bone Marrow Cells; Humans; Leukemia; Signal Transduction; Tumor Microenvironment
PubMed: 34206957
DOI: 10.3390/ijms22136888 -
Experimental Hematology Aug 2015The last few years have seen the identification of bromodomain and extraterminal (BET) proteins as critical mediators of transcription with effects on its direct control... (Review)
Review
The last few years have seen the identification of bromodomain and extraterminal (BET) proteins as critical mediators of transcription with effects on its direct control and cisregulation. This discovery is important in furthering our understanding of the mechanisms of normal transcriptional control. Subsequent work has shed light on the multiple roles of BET proteins in various aberrant transcriptional pathways that have significant implications across many malignant cell types and other disease processes. Accordingly, considerable effort has been made to assess the utility of targeting BET proteins with specific small molecules in acute leukemia and across other types of cancer. In this review, we will discuss the most recent advances in our understanding of the mechanistic actions of BET proteins in normal transcriptional control, both at the gene body and cisregulatory elements; how this is subverted; and its aberrant downstream effects, specifically in the context of acute leukemia and other hematologic cancers. In particular, we will focus on altered epigenetic programs that have been shown to be central to the development and maintenance of acute myeloid leukemia in preclinical models. Finally, we will explore how the use of small-molecule BET inhibitors in leukemias has demonstrated significant promise in numerous single-agent and combination therapy preclinical models and will highlight efforts to translate this promise to the therapeutic arena through various clinical trials attempting to validate efficacy and safety. The considerable opportunities in epigenetically targeting leukemias through BET inhibition will undoubtedly play an important role in improving the management of these conditions in the future.
Topics: Antineoplastic Agents; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Leukemia; Neoplasm Proteins; Transcription, Genetic
PubMed: 26163798
DOI: 10.1016/j.exphem.2015.06.004 -
Journal of Hematology & Oncology Mar 2017The inhibition of the DNA damage response (DDR) pathway in the treatment of cancers has recently reached an exciting stage with several cell cycle checkpoint inhibitors... (Review)
Review
The inhibition of the DNA damage response (DDR) pathway in the treatment of cancers has recently reached an exciting stage with several cell cycle checkpoint inhibitors that are now being tested in several clinical trials in cancer patients. Although the great amount of pre-clinical and clinical data are from the solid tumor experience, only few studies have been done on leukemias using specific cell cycle checkpoint inhibitors. This review aims to summarize the most recent data found on the biological mechanisms of the response to DNA damages highlighting the role of the different elements of the DDR pathway in normal and cancer cells and focusing on the main genetic alteration or aberrant gene expression that has been found on acute and chronic leukemias. This review, for the first time, outlines the most important pre-clinical and clinical data available on the efficacy of cell cycle checkpoint inhibitors in single agent and in combination with different agents normally used for the treatment of acute and chronic leukemias.
Topics: Cell Cycle Checkpoints; Cell Cycle Proteins; DNA Damage; Humans; Leukemia
PubMed: 28356161
DOI: 10.1186/s13045-017-0443-x -
British Journal of Haematology Jan 2020Comprehensive cataloguing of the acute myeloid leukaemia (AML) genome has revealed a high frequency of mutations and deletions in epigenetic factors that are frequently... (Review)
Review
Comprehensive cataloguing of the acute myeloid leukaemia (AML) genome has revealed a high frequency of mutations and deletions in epigenetic factors that are frequently linked to treatment resistance and poor patient outcome. In this review, we discuss how the epigenetic mechanisms that underpin normal haematopoiesis are subverted in AML, and in particular how these processes are altered in childhood and adolescent leukaemias. We also provide a brief summary of the burgeoning field of epigenetic-based therapies, and how AML treatment might be improved through provision of better conceptual frameworks for understanding the pleiotropic molecular effects of epigenetic disruption.
Topics: Adolescent; Child; Drug Resistance, Neoplasm; Epigenesis, Genetic; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Mutation
PubMed: 31804725
DOI: 10.1111/bjh.16361 -
Blood Oct 1987Radiation-induced leukemia is considered to be similar to the de novo disease. However, following an analysis of clinical and hematological findings in leukemia...
Radiation-induced leukemia is considered to be similar to the de novo disease. However, following an analysis of clinical and hematological findings in leukemia occurring in irradiated cervical cancer patients, adult Japanese atomic-bomb survivors, and spondylitics treated with x-ray, striking differences were noted. Acute leukemias in cervical cancer patients and Japanese survivors were similar in type to acute de novo leukemias in adults. Cell types among spondylitics were very dissimilar; rare forms, eg, acute erythromyelocytic leukemia (AEL) and acute megakaryocytic leukemia, were increased. Pancytopenia occurred in 25 of 35 cases and erythromyelodysplastic disorders were noted in seven of 35 acute cases. The leukemias and myelodysplastic disorders closely resembled those occurring in patients treated with alkylating agents. This similarity suggests a common pathogenesis involving marrow stem cell injury and extra-medullary mediators of hematopoiesis. Investigation of early acute leukemias and myelodysplastic disorders with newer techniques may provide valuable insights into the pathogenesis of leukemia in humans.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Leukemia, Myeloid, Acute; Leukemia, Radiation-Induced; Male; Middle Aged; Myelodysplastic Syndromes
PubMed: 3477299
DOI: No ID Found -
Clinical Medicine (London, England) May 2022Acute leukaemia is characterised by uncontrolled expansion of immature leukocytes, either myeloid or lymphoid progenitors, leading to acute myeloid leukaemia (AML) and...
Acute leukaemia is characterised by uncontrolled expansion of immature leukocytes, either myeloid or lymphoid progenitors, leading to acute myeloid leukaemia (AML) and acute lymphoid leukaemia (ALL), respectively. If left untreated, it is life-threatening and can lead to death within weeks. When acute leukaemia is suspected, urgent haematology input should be sought. Appropriate investigations are needed promptly to confirm diagnosis and start treatment. A multidisciplinary approach is vital to ensure appropriate management.
Topics: Acute Disease; Humans; Leukemia, Myeloid, Acute
PubMed: 35584840
DOI: 10.7861/clinmed.2022-0149 -
Leukemia Jan 2018CK2 is a ubiquitously expressed, constitutively active Ser/Thr protein kinase, which is considered the most pleiotropic protein kinase in the human kinome. Such a... (Review)
Review
CK2 is a ubiquitously expressed, constitutively active Ser/Thr protein kinase, which is considered the most pleiotropic protein kinase in the human kinome. Such a pleiotropy explains the involvement of CK2 in many cellular events. However, its predominant roles are stimulation of cell growth and prevention of apoptosis. High levels of CK2 messenger RNA and protein are associated with CK2 pathological functions in human cancers. Over the last decade, basic and translational studies have provided evidence of CK2 as a pivotal molecule driving the growth of different blood malignancies. CK2 overexpression has been demonstrated in nearly all the types of hematological cancers, including acute and chronic leukemias, where CK2 is a key regulator of signaling networks critical for cell proliferation, survival and drug resistance. The findings that emerged from these studies suggest that CK2 could be a valuable therapeutic target in leukemias and supported the initiation of clinical trials using CK2 antagonists. In this review, we summarize the recent advances on the understanding of the signaling pathways involved in CK2 inhibition-mediated effects with a particular emphasis on the combinatorial use of CK2 inhibitors as novel therapeutic strategies for treating both acute and chronic leukemia patients.
Topics: Animals; Apoptosis; Casein Kinase II; Cell Proliferation; Humans; Leukemia; Protein Kinase Inhibitors; Signal Transduction
PubMed: 28951560
DOI: 10.1038/leu.2017.301