S C I E N C E

 Granulocytes

These cells are on the spectrum of white blood cells and in fact they are the most abundant type of white cells. Granulocytes are characterized by the appearance of granules in their cytoplasm which get different colors according to each subtype. Everything starts off with HSC which will later evolve into a multipotent progenitor cell  which even though has a less strong proliferation ability than HSC, it has the ability to differentiate into any type of cell in our body. (For example, we saw in the previous article, how MPP with EPO and other types of molecules will eventually develop into erythrocytes). Here MPP will give off a common progenitor cell of the myeloid cell line (CMP). Furthermore, this progenitor cell will also differentiate into another progenitor cell, the granulocyte/macrophage cell (GMP). To continue, GMP will differentiate into a progenitor of eosinophils (EoP) and a progenitor of basophiles/ mast cells (BMCP). From BMCP other progenitors will be developed, which are the progenitor of mast cells (MCP) and the progenitor of basophiles (BaP).  In the end, myeloblast will be developed.

Myeloblast

Its nucleus occupies most of the cell’s place. The cytoplasm seems light bluish without granules. Three to four nucleoli can be seen. Its size can vary from 15-20 μm. Eventually, myeloblast will differentiate into promyelocyte.

http://histology-world.com/photoalbum/displayimage.php?album=65&pid=3478

Promyelocyte

We can see more promyelocytes than myelocytes in the bone marrow. In addition, its cytoplasm has gained more space than its progenitors. Also, some primary granules are able to be seen. There still can be observed some nucleoli more abstractly though. Its size surprisingly can vary from 15 to30 μm and it is the only exception of the rule. (Generally, the produced cells are smaller than their progenitors). Promyelocyte will differentiate into myelocyte.

https://medical-dictionary.thefreedictionary.com/promyelocyte

Myelocyte

 

Hematopoiesis is the process where the mature blood cells of our body are produced. This procedure begins in the embryonic stage and every cell develops from the hematopoietic stem cells (HSCs). It should be noted that there are five different types of stem cells:

Totipotent (or Omnipotent) Stem Cells: They are the most powerful ones since they have the ability to differentiate into embryonic and extra embryonic types of cells like the placenta. In other words, they can produce each cell in our bodies and form a whole new organism.

Pluripotent Stem Cells: These cells are considered the "offspring" of totipotent stem cells. They can also develop into any kind of cell in our body, but they cannot form extra outer embryonic tissues.

Multipotent Stem Cells: They have the ability to differentiate into relative cells of the same tissue, like for instance the erythrocytes, leukocytes, platelets etc.

Oligopotent Stem Cells:  These stem cells can differentiate into cell types of the same cell line. Such examples are the myeloid stem cells.

Unipotent Stem Cells: They can only produce one type of cell, since they have the lowest differentiative potential.  For instance, they can only produce sperm cells.

There is a general rule applied during cell differentiation. Every new cell line that is produced, gradually shrinks is size, the nucleus becomes smaller while the cytoplasm gets bigger.

Basophil Erythroblasts

The cytoplasm can get colored as blue, there are high levels of RNA and the nucleus has gotten a bit smaller. The euchromatin is visible and we can see it with a pinkish color. Lastly, Basophil Erythroblasts can appear with an irregular shape and with pseudopods.

After the first mitosis two polychromatophilic erythroblasts(normoblasts)  will be produced.

https://slidetodoc.com/erythroid-maturation-proerythroblast-basophilic-erythroblast-polychromatophilic-erythroblast-acidophilic/

Polychromatophilic Normoblast

The cytoplasm has now gotten a greyish color, mainly because the RNA has decreased and there is also the addition of erythropoietin. Furthermore, the nucleus has been reduced a bit more in size. Also, here the appearance of heterochromatin is observed, with a blue color while the euchromatin holds a pink-red color. After two mitosis, four orthochromatic normoblasts will be produced.

 

https://era.library.ualberta.ca/items/676869c8-1256-4bfe-be4f-3bb82b8c9de6

Orthochromatic Normoblasts

In this cell type, there is an increased production of erythropoietin and the cytoplasm is starting to become less and less visible with a small number of polyribosomes. Also, the nucleus is small and dense and there are cytoplasmic folds. It is important to note that this cell does not go through division. It only matures.  

https://era.library.ualberta.ca/items/7ceb86a8-4623-40a6-acbb-16e260c048a0

Reticulocyte

After the orthochromatic normoblast’s maturation (expels the nucleus) we have the formation of reticulocytes. They do not have a nucleus, but they consist of many ribosomes because it composes erythropoietin. Gradually, the ribosomes and mitochondria will disappear, and erythropoietin’s production will stop.  Reticulocytes are bigger than the cells that will be generated after them and there are more of them in the bone marrow than in the blood (in a healthy organism). In fact, they remain in the bone marrow for one to two days.

https://www.jaypeedigital.com/book/9789386107671/chapter/ch16

Erythrocytes

From erythrocytes, we have the production of mature erythrocytes after the reticulocyte enters the blood circulation. 

https://www.youtube.com/watch?v=bbUlaTApuuI

Important stages of erythropoiesis

Sources

-My own notes

-Pediatric hematology -Oncology by Fotini Tzortzatou-Stathopoulou

-https://www.sciencedirect.com/topics/medicine-and-dentistry/hematopoiesis

-http://kremiotis.mysch.gr/BlastikaKyttara.pdf

 

 During my own personal effort to try and understand the differences that many types of leukemias have, I decided to write some sequent articles explaining each type as much as I can. Starting off with the word I have been watching in every book and article that I have read, and it is as a matter of fact a Greek word. Leukemia (in Greek Λευχαιμία) origins the two Greek words white (λευκός) and blood (αίμα). In other words, the word itself explains the main problem of this cancer type: there is a dysfunction in the progress of differentiation and the maturation of white blood cells. As a matter of fact, leukemias characterize a type of cancer within the blood and in the bone marrow influencing different white blood cells each time (or many at a time).

 

Chronic eosinophilic leukemia (CEL)

Chronic eosinophilic leukemia is a disease which belongs to myeloproliferative syndromes. These syndromes refer to pathological conditions and their “root of problem” begins in the stem cells. Unlike myelodysplastic conditions, which show several morphological disorders, myeloproliferation involves the increase of the cell number. Starting from the primitive cell clones in the bone marrow, we have stem cell hyperplasia of some cell lines. Specifically, it refers to the problematic proliferation of granulocytes, red cells, and megakaryocytes. It does not involve lymphocytes.

Chronic eosinophilic leukemia is caused by the primal clone of eosinophils. There have been observed, eosinophils in the marrow and blasts circulating in the blood and marrow. Some immature forms of eosinophils such as myelocytes and post-myelocytes are also seen, as well as a granular turn to the left. This basically means the presence of metamyelocytes and other earlier cell forms of the granular line in the blood. As a result, in the myelogram we can see an image of a hyperplastic marrow, filled with earlier forms of eosinophiles.

 

What causes this CEL?

The exact cause is not yet known but the aftermath, this cause has created it in the body has been studied. Starting off with the explanation of a common disorder that has been observed in many myeloproliferative neoplasms. Studies have shows that the BFU-E colonies appear to have an increased sensitivity to growth factors. Under normal conditions, erythropoietin binds to its receptor and activates the jack2 molecule, which will start the phosphorylation signal to factor T. This factor will activate other transcription factors to initiate red blood cell production. However, in myeloproliferative syndromes, there is a mutation in the Jak2 gene which results in the absence of repressive mechanisms for the deactivation of the gene. In consequence, the Jak2 gene is constantly activated. Based on a similar process the chronic eosinophilic leukemia is made. Here, we have the deletion of a large part of the genome. This leads to the creation of a hybrid gene, FIP1L1-PDGFRa, which has a similar role to Jack2. Eventually, this hybrid that has been created, is an overactive kinase, {kinases role is to transfer phosphate groups} but this kinase is constantly and overly activated, and the transfer of the phosphor will set off other signals for even more molecules to be created. Because of this procedure, much more transcription factors will be activated, and they will induce cells proliferation.

            https://www.pathologyoutlines.com/topic/myeloproliferativeCEL.html

Chronic Myeloid Leukemia (CML)

Myeloid Leukemia falls under the category of myeloproliferative disorders just like Chronic Eosinophilic leukemia. However, it is considered to be a different disease with other type of symptoms and findings.

Starting off with the pathological discoveries, this neoplasm appears with splenomegaly and anemia. In the blood, an increased number of white blood cells {basophils, eosinophils and sometimes platelets} and immature cells of the myeloid cell line have been observed. In the bone marrow, it has been discovered that the myeloid lines development is normal but there is hyperplasia of granulocytes (with some elements of dysplasia of the basophils and eosinophils). As it is expected, a rise in the number of megakaryocytes have also been seen.

Question1: Why there are immature cells of myeloid cell line in the blood, when in the same time bone marrow appears with a normal development of that line?

 

Genetic findings

The exact reason is still unknown, but discoveries of genetic disorders have shown some light in the research. There is a fracture of the chromosome 9. Basically, a rearrangement takes place between chromosomes 9 and 22 which results in a breaking of ABL and BCR genes. This “rapture” creates a new hybrid gene called BCR-ABL in the 22 changed chromosome, which is now called Philadelphia chromosome.

The BCR-ABL hybrid gene activates Jak stat pathway (this pathway is activated in most myeloproliferative syndromes due to Jak2 mutation). BCR-ABL activates the production of IL3 and GCSF which will later activate Jak kinase. Both of these kinases, phosphorylate STAT5 which is a transcription factor and will eventually lead in cell proliferation. Additionally, BCR-ABL participates in much more procedures, like apoptosis. In fact, with sequent phosphorylations it suspends the apoptosis. Both of those two BCR-ABL traits that have been mentioned, create an environment where cell proliferation without death can bloom.

Bcr-Abls protein has some qualities which are worth mentioning. The protein p210Bcr-abl enables the intracellular signal transduction pathways by cell deregulating the cell cycle through uncontrolled proliferation, suspend the apoptosis with the result of the appearance of more cells in the marrow and prevents cell adhesion the bone marrows layer and that is why blasts are seen in the blood flow, since they cannot stay attached to their normal environment.  (answer to question1)

 

Categorization of CML

This disease can be divided in two three different stages according to its progression.

 Chronic phase

The chronic phase of CML is characterized by blasts both in the blood and in the marrow less than 10%. It can last from 5 to 6 years and it ranges from asymptomatic to mild symptoms. The appearance of marrow is obviously disturbing with dysplasia in the granulocyte line with increased myelocytes.

 

                                                        Normal Bone marrow , Hematoxylin & Eosin stain

                            Chronic phase oh CML, Bone marrow , dysplastic megakaryocytes 

                             Chronic Phase of CML (bone marrow), increased eosinophils

                            http://imagebank.hematology.org/image/2823/chronic-phase-cml--1

Accelerated Phase

Here, an increased number in white blood cells (especially basophils & eosinophils) and in blasts (10-19% both in blood and marrow). In addition, this stage is characterized by the detection of some cytogenetic mutations such as duplication of Philadelphia chromosome, trisomy 8, isochromosome 17q, trisomy19 and myelofibrosis. It can last from 6-9 months and the symptoms emerging include splenomegaly, anorexia, and bone pain.

                    Accelerated Phase: the bone marrow appears with an increment in blasts.

                http://imagebank.hematology.org/image/2394/accelerated-phase-cml--2?type=upload

                           Accelerated phase in Bone marrow. Dysplastic changes can be seen.

                    http://imagebank.hematology.org/image/2819/accelerated-phase-of-cml--8

Blasts Crisis

In this final stage, we can observe severe hematological disorders with the blasts in the blood and in the marrow exceeding the 19% of the totally white blood cells. One feature of this stage is the extramedullary proliferation of blasts appearing in big masses all together. A person suffering from CML in this stage can last without therapy from 3 to 6 months only. The symptoms range from vary severe weakness, pain, and difficulty in breathing.

Sources :