Clonal hematopoiesis and non-hematologic disorders

Jaiswal, Siddhartha

doi:10.1182/blood.2019000989

Cited by 96 publications

(116 citation statements)

References 110 publications

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“…Although the mechanistic link between CH and this large number of various disorders remains to be elucidated, CHassociated inflammation appears as the overarching principle. Diverse mediators of innate and adaptive immunity have been described to be modulated by the occurrence of specific CH-associated somatic mutations [65,66]. Not only cellular components of the myeloid lineage like monocytes/macrophages [56,[67][68][69][70], mast cells [71], neutrophils [72], but also lymphatic cells [73][74][75][76][77] can exert altered function.…”

Section: Introductionmentioning

confidence: 99%

Clonal hematopoiesis and its emerging effects on cellular therapies

et al. 2021

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The accumulation of somatic mutations in hematopoietic stem cells during aging, leading to clonal expansion, is linked to a higher risk of cardiovascular mortality and hematologic malignancies. Clinically, clonal hematopoiesis is associated with a pro-inflammatory phenotype of hematopoietic cells and their progeny, inflammatory conditions and a poor outcome for patients with hematologic neoplasms and solid tumors. Here, we review the relevance and complications of clonal hematopoiesis for the treatment of hematologic malignancies with cell therapeutic approaches. In autologous and allogeneic hematopoietic stem cell transplantation native hematopoietic and immune effector cells of clonal origin are transferred, which may affect outcome of the procedure. In chimeric antigen receptor modified T-cell therapy, the effectiveness may be altered by preexisting somatic mutations in genetically modified effector cells or by unmodified bystander cells harboring clonal hematopoiesis. Registry studies and carefully designed prospective trials will be required to assess the relative roles of donor- and recipient-derived individual clonal events for autologous and allogeneic cell therapies and to incorporate novel insights into therapeutic strategies.

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Section: Introductionmentioning

confidence: 99%

Clonal hematopoiesis and its emerging effects on cellular therapies

et al. 2021

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“…A recent study showed that stress-induced repeated HSC activation can lead to DNA damage in HSCs eventually obliterating hematopoiesis in mice [ 54 ]. Regarding mutations the concept of clonal hematopoiesis has been developed which is associated to malignant and nonmalignant diseases [ 55 , 56 ]. Such clonally expanding stem/progenitor cells can affect the original stem cell pool, or even take over hematopoiesis completely in humans [ 57 ] eventually decreasing its heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Implications of hematopoietic stem cells heterogeneity for gene therapies

Epah

Schäfer

2021

Gene Ther

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Hematopoietic stem cell transplantation (HSCT) is the therapeutic concept to cure the blood/immune system of patients suffering from malignancies, immunodeficiencies, red blood cell disorders, and inherited bone marrow failure syndromes. Yet, allogeneic HSCT bear considerable risks for the patient such as non-engraftment, or graft-versus host disease. Transplanting gene modified autologous HSCs is a promising approach not only for inherited blood/immune cell diseases, but also for the acquired immunodeficiency syndrome. However, there is emerging evidence for substantial heterogeneity of HSCs in situ as well as ex vivo that is also observed after HSCT. Thus, HSC gene modification concepts are suggested to consider that different blood disorders affect specific hematopoietic cell types. We will discuss the relevance of HSC heterogeneity for the development and manufacture of gene therapies and in exemplary diseases with a specific emphasis on the key target HSC types myeloid-biased, lymphoid-biased, and balanced HSCs.

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“…However, driver mutations in HSCs leading to CH may also give rise to overproduction of mutated immune effector cells, such as monocytes, granulocytes, and lymphocytes. These effector cells can potentially influence many disease states, especially those with a chronic inflammatory component [126], resulting in elevated disease risk. In polycythemia vera and essential thrombocytemia, blood diseases belonging to a rare type of CH with pathological manifestations [127], overproduction of erythrocytes and thrombocytes results in a highly increased incidence of thrombotic events [128].…”

Section: Distance To the Endosteum Proliferative Potential Predominance Of Myeloid Differentiation Bm Homing Mobilization By Cytokinesmentioning

confidence: 99%

Hematopoiesis during Ontogenesis, Adult Life, and Aging

Belyavsky

Petinati

2021

IJMS

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In the bone marrow of vertebrates, two types of stem cells coexist—hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Hematopoiesis only occurs when these two stem cell types and their descendants interact. The descendants of HSCs supply the body with all the mature blood cells, while MSCs give rise to stromal cells that form a niche for HSCs and regulate the process of hematopoiesis. The studies of hematopoiesis were initially based on morphological observations, later extended by the use of physiological methods, and were subsequently augmented by massive application of sophisticated molecular techniques. The combination of these methods produced a wealth of new data on the organization and functional features of hematopoiesis in the ontogenesis of mammals and humans. This review summarizes the current views on hematopoiesis in mice and humans, discusses the development of blood elements and hematopoiesis in the embryo, and describes how the hematopoietic system works in the adult organism and how it changes during aging.

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Clonal hematopoiesis and non-hematologic disorders

Cited by 96 publications

References 110 publications

Clonal hematopoiesis and its emerging effects on cellular therapies

Clonal hematopoiesis and its emerging effects on cellular therapies

Implications of hematopoietic stem cells heterogeneity for gene therapies

Hematopoiesis during Ontogenesis, Adult Life, and Aging

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