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Bhavuk Garg
Bone marrow is soft trabecular tissue nourished by an intensive network of blood vessels. This tissue is found in axial and leg bones of the body. Bone marrow is primarily made up of two types: red bone marrow and yellow bone marrow. Red bone marrow contains stem cells and is the site for generation of blood cells by a process called hematopoiesis. This consists of both red blood cells and white blood cells. While red blood cells mainly contain RBCs, white blood cells include B and T-lymphocytes, granulocytes, and platelets. Yellow bone marrow comprises fat cells, mesenchymal stem cells, chondrocytes, endothelial cells, osteoblasts, and osteoclasts. This is also called stroma and provides the microenvironment to facilitate hematopoiesis. Here I will discuss the loss of bone marrow function and its physiological implications, followed by how it may lead to leukemic progression.
The architecture of blood vessels, red bone marrow, and white bone marrow leads to its organization of specific bone marrow compartments called niches. These niches result in a microenvironment that provides nourishment and stimulatory factors for proliferation, differentiation, and maturation of stem cells into RBCs, white blood cells, and platelets. Niches play a vital role in bone marrow functions, such as hematopoiesis by providing specific responses to diverse stimuli and delineating the maturation of different types of blood cells. Hematopoiesis is a highly regulated sequential process for the synthesis of blood cells that occurs in the bone marrow. Thus, red and yellow bone marrow together maintain the blood constitution and bone health. They also provide the necessary stimulus for emergency hematopoiesis in case of injury or infection.
Dysfunction of the primary physiological function of bone marrow, hematopoiesis, is known as bone marrow failure (BMF). This breakdown of hematopoiesis in bone marrow may be general or blood cell type/lineage-specific. Bone marrow failure may be inherited or acquired. Inherited bone marrow failure is a set of rare childhood disorders that occur due to mutations, either germline from parents or de novo by chance. Acquired bone marrow failure is an adult syndrome that may be due to exposure to viruses, toxins, chemicals, or maybe therapy related.
BMF may result in a decrease if a single lineage of cells, called cytopenia, or multiple cell types called pancytopenia. This presents itself in tiredness, weakness, pallor, breathlessness, tachycardia in the case of abnormally low RBCs, recurrent or severe bacterial infections upon loss of white blood cells. A decrease in the number of platelets leads to easy bruising, and bleeding from the nose and/or gums.
BMFs have a high likelihood to progress to myelodysplasia, which is characterized by morphological and functional changes in one or more blood cell lineages, and ineffective hematopoiesis. This may manifest in blood cancers such as acute myeloid leukemia.
Bone marrow transplantation (BMT) is the most effective treatment for BMF, whereby matched, related donor’s bone marrow is used to replace the pathologic bone marrow of the patient which has been ablated by radiation or chemotherapy. However, the complications associated with BMT, as well as the possibilities of rejection argue for alternative approaches. Pharmacological interventions are based on the pathogenesis of BMF in a patient. For an autoimmune disorder where bone marrow is attacked by its own cells, immunosuppression is used. Hematopoietic growth factors are used to stimulate lineage-specific blood cell growth.
The efficacy of treatment for bone marrow failure depends on the identification of molecular mechanisms of these syndromes. The lack of appropriate model systems is a major hindrance in understanding the pathways associated with the pathological or chemical induction and mutations linked to BMFs. Further research to determine specific mechanisms of disease pathogenesis shall inform better treatment strategies and will be able to serve as an alternative to bone marrow transplants.
Edited by Rachel Cherney
Photo credits: Follicular Lymphoma in Bone Marrow, Flickr
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