User:Immcarle151/Monoblast

Copy from [Monoblasts]

Monoblasts are the committed progenitor cells that differentiated from a committed macrophage or dendritic cell precursor (MDP ) in the process of hematopoiesis. They are the first developmental stage in the monocyte series leading to a macrophage. Their myeloid cell fate is induced by the concentration of cytokines they are surrounded by during development. These cytokines induce the activation of transcription factors which push completion of the monoblast's myeloid cell fate. Monoblasts are normally found in bone marrow and do not appear in the normal peripheral blood. They mature into monocytes which, in turn, develop into macrophages when they reach the site of infection. They then are seen as macrophages in the normal peripheral blood and many different tissues of the body. Macrophages can produce a variety of effector molecules that initiate local, systemic inflammatory responses. These monoblast differentiated cells are equipped to fight off foreign invaders using pattern recognition receptors to detect antigen as part of the innate immune response.

STRUCTURE

A typical monoblast is about 12 to 20 μm in diameter, has a nuclear to cytoplasm ratio of 4:1 to 3:1, and, like most myeloid blasts, has a round to oval nucleus with fine chromatin structure. Compared to other myeloid blasts, monoblasts have more cytoplasm. The nucleoli it contains is usually distinct. One to four nucleoli are usually visible. The nucleus can be central or eccentric and it can show evidence of indentation or folding. The cytoplasm stains moderately to lightly basophilic and may contain small azurophilic granules. These granules contain enzymes that can damage or digest pathogens and also release inflammatory signals in the periphery. Auer rods are there, but rarely seen. Easily observed in the round monoblast nucleus is lacy, clear chromatin and distinct nucleoli.

Development

The monoblast is the first stage of monocyte-macrophage maturation. The developmental stages of the monoblast are: CFU-GM (pluripotential hemopoietic stem cell or hemocytoblast) -> monoblast -> promonocyte -> monocyte-> macrophage/dendritic cell. During their development, monocytes are present in large pacts in all of the lymph nodes in the body.

Hemopoietic stem cells mature into monoblasts by being in a concentrated environment of certain cytokines that induce activation of certain transcription factors. The development of monoblasts occurs when certain transcription factors are activated, crucial ones being PU.1 and GATA1. Development continues by, yet again, the concentration of transcription factors in the environment. A monoblast matures into a monocyte if the transcription factors PU.1 and C/EBPa surround it.

Monocytes will then develop into macrophages or dendritic cells upon tissue damage and recruitment of monocytes into the infected area. During recruitment monocytes are distinct from macrophages and dendritic cells, but upon entering the infected area, monocytes will acquire inflammatory effector functions and then differentiate into inflammatory cells such as macrophages or dendritic cells. These inflammatory cells are now better equipped to combat a foreign invader quickly (in the case of macrophages) and specifically (in the case of a dendritic cell) through activating different parts of the Immune response.

ACUTE MONOYCitic Luekemia

copy from acute monocytic leukemia:

Acute monocytic leukemia (AMoL, or AML-M5) is a type of acute myeloid leukemia. In AML-M5 >80% of the leukemic cells are of monocytic lineage. This cancer is characterized by a dominance of monocytes in the bone marrow. There is an overproduction of monocytes that the body does not need in the periphery. These overproduced monocytes interfere with normal immune cell production which causes many health complications for the infected individual.

Causes: The pathology of AML involves abnormal proliferation and differentiation of a population of myeloid stem cells. Genetic mutations are identified in the majority of cases. A common genetic mutation identified in these cases are characterized as chromosomal translocations where information from one chromosome is exchanged to a non-homologous chromosome creating an unusual rearrangement of chromosomes. This translocation is often abbreviated as t(#of one chromosome involved, #of other chromosome involved). M5 is associated with characteristic chromosomal abnormalities, often involving chromosome 11, such as t(9;11), affecting the MLL (KMTA2) locus at 11q23; however, MLL translocations are also found in other leukemia subtypes. The t(8;16) translocation in AMoL is associated with hemophagocytosis. These translocations yield the formation of chimeric proteins (RUNX1-RUNX1T1 and PML-RARA, respectively) which disrupt normal myeloid precursor development.

Secondary leukaemia, which may include AML-M5, has been associated with exposure to epipodophyllotoxins, such as etoposide.

Many cases of AML-M5 are seen to have enhanced phosphorylation of the STAT3 protein due to increased induction of cytokines thus increasing cell proliferation and survival. Finally, genetic mutations involved in epigenetic regulation are associated with this leukemia, as they has downstream effects on cell differentiation and proliferation. Excessive cytokine release could be a byproduct of skewed epigenetic regulation.

AML-M5 is treated with intensive chemotherapy (such as anthracyclines) or with bone marrow transplantation. Tyrosine kinase receptor inhibitors are a prominent treatment developed to combat the over activation of cell proliferation proteins induced by AML-5. Inhibiting the STAT3 protein is another useful form of treatment.