S C I E N C E

 

The product is the result of a left nephrectomy and its size with the perinephric fat is 19x10x8 cm. It is partially covered by the Gerota’s fascia. Also, it connects with the ureter which is 3 cm long with maximum size of 0,5 cm. After the kidney had been cut its dimension were 1,5 x 2 cm.  There is an observation of an orange but partially reddish solid and partly spongy neoplastic tumor, measuring 7x6x4 cm. The tumor is located in middle of the kidney,  0,1 cm at distance from the renal pelvis and 1 cm away from the renal capsule. Additionally, the neoplastic growth reaches closely to the perimetric capsule and to the perimetric renal fat. The rest of the kidney’s area maintains a medullary architecture and the product weights 414 kg.

                                                    Sigmoid Colon

                                      sigmoid colon (after being opened). The tumors are visible.

 Cancer is a disease like no other. We cannot compare it with an intruder because it is not an outside "genome" or an uninvited virus. Cancer cells start from within us, and I would dare to say that they are a part of us. They are us. Let's take an example of a person who suffers from a personality disorder. Some days, the individual behaves like their normal self and take care of their health. Some other days however, their disorder takes over, creating another character which attacks his own body. The person becomes an enemy of their own self. That is exactly how I would describe cancer. Likewise, cancer cells are our own cells that have undergone specific modifications.

It is important to note that our immune system has a mechanism called central tolerance which eliminates through the process of apoptosis, T and B cell clones before their maturation, only if they have receptors that recognize antigens (molecules) of the same organism with an affinity greater than one limit. Basically, this means that when some cells are produced that seem to deviate from the norm and include indicators about their abnormality, our system will recognize them and kill them. However, central tolerance is not infallible, and some self-reactive lymphocytes escape to the secondary lymph tissues. That is the reason why there is an additional security mechanism called the peripheral tolerance.

Taking all this process into consideration, could these or similar mechanisms eliminate potential cells that are prone to forming cancerous tumors?

NK cells: They have the ability to attack on any cell in the body that expresses abnormal or unusual proteins in its cytoplasmic membrane and thus they can destroy some cancer cells.

CTLs: their cytotoxic action enables them to destroy cancer cells.

In contrast of what these cells can do, cancer cells are still able to grow and keep multiplying. That happens because cancer cells end up being cleverer than NK and CTLs by developing mechanism allowing them to evade immune responses.  Similarly, the microenvironment surrounding tumor cells suppress the functions of our tolerance by tricking our immune response resulting in an uncontrolled cancer growth.

After a lot of observation, a simple question started spiraling in my head:  Do normal cells “give birth” to a cancerous offspring or the normal cell must first have some alterations itself, ending up in an between state of normal and non-normal in order to “create” the next generation of malignant cells? And if so, the in between state of this cell, could be the reason why it is easy for it to trick our immune system?

There have been some indicators that prove the existence of state called transformation. A cell that is transformed appears with alterations in its morphology. In some cases, this state can make the cell form tumors. The cell transformation is caused by mutations due to DNA alkylation agents such as busulfan, cyclophosphamide, dihydroxybusulfan or due to natural cytotoxic causes like ionizing radiation.

The first stage of the cancerous transformation consists of genetic mutations and after, the existence of some promoters which will define the direction of the transcription and will induce cell division will be the cause of the “produced cancerous offspring”. In a hypothetical scenario, where a transformative cell exists without its promoters, then there will be no cancer. Can a gene promoter ignore mutated genes and give the signal for the transcription to start after these regions? And if these regions are of outmost importance for the transcription to take place, then could the promoter or another molecule recognize the changes, and trigger apoptotic signals? Could we create such signals in the laboratory and insert them in one’s organism in order for them to detect suspicious transformed cells?

Although I have mentioned it before, some potential ways  one’s cells could undergo gene mutations, I must pay attention to the danger of some viruses. Some cancer types have been confirmed to be caused by a specific virus, even though some other types {such as leukemias} are considered still to be the result of an unknown agent. I personally have a belief that most of the cancer types are generated by a virus either to the person who suffers from cancer or from one of his ancestors. {This will be discussed in another article}.

Lets take an example of Simian vacuolating virus 40 (SV40). The virus after entering the human body, has his genome to be incorporated to the hosts DNA. The SV40 virus codes two prime proteins called large T and small T and both will initiate the cancerous cells transformation of the cells that have been infected by SV40.

Some other viruses that are related to carcinogenesis are: Epstein-Barr, HBV, Human T-lymphotropic virus type 1, Human herpesvirus-8 (HHV-8).

The last two viruses mentioned, are RNA viruses and in some cases, they contain peculiar genes called oncogenes. Let’s take an example of the Rous sarcoma virus which includes in its genome a specific oncogene named v-src.

V-src will code a protein kinase which will phosphorylate tyrosine residues in proteins. It has been shown that this process will activate the STAT family which has a very important role in growth factor, the RAS signal  {RAS/MAP is an intracellular signal molecule that induces cell proliferation and the existence of mutations in this molecule promote carcinogenesis} also mutations in the RAS molecule are detected in 30% of ALL and in 15% in MDS. This will result in a constant cell proliferation, mutations, and abnormalities in chromosomes.

{Could we deactivate the V-src gene in cancer cells in vivo?}

There have been some indications that oncogenes are not only produced by viruses.  In particular, Howard Temin, suggested that oncogenes can actually “live” in healthy cells and actually the virus can take these oncogenes from the host’s genome.  The host’s oncogenes were called proto-oncogenes or cellular oncogenes. In other words, proto-oncogenes, are genes which after mutation become oncogenes causing tumor growth. The main difference between proto-oncogenes and oncogenes is that proto-Oncogene are normal cells existing in an individual’s genome and they control the cell cycle and the cell division. They can be proteins regulating cell growth control, growth factors, growth factor’s receptors, signal transducers, intranuclear agents, regulators of cell dead. On the other hand, oncogenes are the malicious form of cellular oncogenes, often being created after mutations caused by ionized radiation, drugs or viral genome insertion. A oncogene caused by an RNA virus can contribute to the formation of viral oncogenes while oncogenes created by mutations and drugs can result in the creation of a modification in their expression such as overactivated proteins or an increased or decreased quantities of important factors.  Some examples of proto-oncogenes are the RAS molecules, Myc, Her2. Different kind of mutations can occur that will transform cellular oncogenes into oncogenes such as deletions, chromosomal translocations, point mutations, or extra chromosomal copies of a proto-oncogene.

Additionally, oncogenes have been classified in different subtypes regarding their role.

Starting off with one type of proto-oncogenes and their oncogenes which encode proteins that provoke cell proliferation. As a matter of fact, some of these proteins operate as growth factors or their receptors. One example of such oncogenes is the SIS oncogene of simian sarcoma virus (SSV) which can be found in the human malignant glioma. SIS will encode a form of platelets growth factor PDFG. Similarly, the erbB gene will encode a growth factors receptor, homologous to the EGF receptor. As it is expected, this inaccurate and different encoding of homologous growth factor or its receptor can result in an uncontrollable proliferation of the cell cycle. Furthermore, a constant encoding of transcription factors can end up in the same unrepressed growth.

Another type of proto-oncogenes are the ones called tumor suppressor genes, reducing the cell division’s speed by slowing it down. They operate with a negative regulation by encoding proteins that will stop the division, as well as trigger apoptosis when it is needed. Equally important is their role in repairing DNA mistakes. If tumor suppressor genes do not work according to their regulations or if they get deactivated DNA is more prone to mistakes, apoptosis is being avoided and cells can grow uncontrollably. A great example to such case, could be the retinoblastoma which is caused by the inheritance of a mutated allele. If the normal allele gets deactivated, then tumor cells will start occurring.

Moving on to the third classification of cellular oncogenes, we have genes holding the responsibility for apoptosis. These specific genes, encode proteins which either can activate or deactivate the process. Apoptosis is a function of extreme importance for our wellbeing. It is the way which the body is able to get rid of the unwanted cells. Not only aged cells can slowly die but also, it prevents from tumor formation and is crucial in immune processes, such as the development of tolerance and the destruction of target cells by cytotoxic T cells or by natural killer cells. For example, when lymphocytes continue to be activated by an antigen, the messages received during activation inhibit the corresponding apoptotic messages. As antigen levels decrease, apoptosis inhibition signals fade and lymphocytes begin to die. If cytotoxic cells do not die through apoptosis when they should, they will start attacking on the normal cells creating autoimmune disorders. An anti-apoptotic gene called  bcl-2 which is an oncogenic gene often found in non-Hodgkin lymphoma. This gene gets activated after a chromosomal translocation t(14;18). Lastly, a correlation was found between bcl-2 and Epstein bar since the virus seems to have a homologous gene which can function with a similar way and induce the apoptosis. Do we know if this similar virus gene existed prior to bcl-2 or it is a confirmation of Howard Temin’s theory where a virus can get its oncogenes from the hosts genome?

 In conclusion, one can say that cancer is a part of us that followed the wrong way. It seems that malignant tumors are not easy to be killed without killing us too. If cancer was triggered by a virus, an atomic bomb which affected near areas with people’s genes undergoing mutations and then inheriting it to their offspring or some specific medications then we could say that it is indeed say that it is an invader that lives silently within us until it suddenly takes its toll. However, could cancer exist without any of these? To be a sincere malfunction of our own cells? 

Sources :

-My own notes

-The book : Kuby Immunology

-https://www.ncbi.nlm.nih.gov/books/NBK547849/

-https://www.nature.com/articles/1203912

-https://www.wikigenes.org/e/mesh/e/19312.html

-https://www.nature.com/scitable/topicpage/proto-oncogenes-to-oncogenes-to-cancer-883/

 

Megakaryopoiesis

Starting off, this procedure begins as it is expected, with the HCS, the multipotent self-renewing cells. HCS will produce a multipotent progenitor (MPP) which is a common progenitor for every cell in our body. This cell will differentiate into our common myeloid progenitor (CMP) which is produce by its turn another cell which is the progenitor of megakaryocytes and erythrocytes (MEP).  Basically, MEP is the cell that will give of either erythroblasts or megakaryocytes. The development of these two, depends on the signals, the factors, and the microenvironment. As a matter of fact, some important transcription factors that must exist in the surrounding in order for the Megakaryopoiesis to start being produced, are GATA-1 is crucial for the differentiation and the maturation of megakaryocytes, FOG-1 which interacts with GATA-1 and activates or deactivates it, GATA-2, Fii-1 , Pu.1 with its decrease being a key to the normal development of megakaryocytes  and RUNX1. The maturation and the final production of platelets take place in specific places in the bone marrow and with the interaction of other molecules and growth factors.

In order for the common myeloid progenitor to start developing towards the megakaryocytes, one important hormone must be present. This molecule is called thrombopoietin, it is produced in the liver and it regulates platelet production.

EMP cells will eventually differentiate into BFU cells and at that time, thrombopoietin is that one molecule that will get activated and help BFU cells differentiate into CFU. BFU and CFU cells are morphologically the same since both of them are immature cells of the bone marrow, however in cultivation, only the CFU cells are able to form colonies.  Eventually, the CFU cells will differentiate into promegakaryoblasts which will give off megakaryoblasts and these cells will mature into megakaryocytes.

Megakaryocyte has pseudopods and a specious cytoplasm. In addition, it is an excessively big cell, and its maturation happens in two stages: The first stage consists of the typical mitosis and in the second, there is the proliferation of the nucleus while the cytoplasm does not get divided (Polyploidy).  This results in a size increasement (by endomitosis).

The pseudopods the megakaryocyte has, will get detached from it , the nucleus will endure apoptosis and will get phagocytized by macrophages. At that time, the cell exists near the venus sinuses and then they will release the platelets in the blood circulation. Platelets have no nucleus, but they consist of vesicles such as lysosomes and alpha granules. 

https://www.sciencedirect.com/science/article/abs/pii/S0037196310000326

 Monocytes & Dendritic cells

Monocytes and dendritic cells are both considered to fall under the spectrum of myeloid cell line. They obviously share the MPP progenitor as all of them cells in our body, and also share the myeloid progenitor cell which will eventually differentiate into the granulocytes/macrophages progenitor (GMP). GMP cell will mature into monocytes/dendritic progenitor (MDG). One molecule which seems to separate which cells will be produced (monocytes or dendtritics) seem to be Ly6C+ cell. It is claimed that this cell appears both in the marrow and in the spleen and triggers the production of monocytes.

 

Monocytes

Monocytes are able to circulate in the blood for about 8 hours, increasing in size. After their enlargement, they migrate to different tissues and differentiate into macrophages. This differentiation process consists of the increment of their  organelles both in size and complexity and they also gain a high phagocytic capacity with the ability to produce higher levels of hydrolytic enzymes and a variety of soluble agents.

 

Dendritic cells

They have elongated cytoplasmic projections on their surface, and they are many different types of those cells.  Their main categories are: Langerhans cells, intracellular space cells, monocyte-derived dendrites, and plasma cell-derived dendrites. Each type of dendritic cells has different functions  of trapping the antigen in one area and presenting it in another place.

 

Lymphopoiesis

Lymphopoiesis is the creation of lymphocytes. These cells circulate all the time in the blood and in the lymph. As a matter of fact, the lymphatic system is one of the most important systems in our body because the lymph, originates from tissues and it slowly filters into the lymph node, piercing the cortex, paracortex and marrow, and gives phagocytes and dendritic cells the ability to trap bacteria or other antigens, which have been transferred by the lymph. If the same antigen invades again into our body, the lymph will immediately leave the lymph node while being filled with antibodies. The lymph that exists the lymph node, contains way more lymphocytes than the lymph that enter the lymph node. Lymphocytes are divided into three main categories: B cells, T cells and NK cells. Basically, those three cells have different molecules on their membranes surface.

T lymphocytes mature in the Thymus and during this procedure the T cell expresses on its membrane a molecule that binds antigens which is called T cell receptor (TCR). Those receptors are able to recognize antigens only when they have been connected with membrane proteins named Major Histocompatibility Complex (MHC) molecules and they are genetically diverse glycoproteins. After an antigen binds with MHC molecules, it will get recognized by some T cells, which will eventually start to multiply and differentiate into effector cells and T memory cells. It is important at this stage to distinguish, the three main different “subpopulation” of T cells: T helper cells, cytotoxic T cells and Regulatory T cells (Tregs).

T helper cells:  These cells contain a surface glycoprotein called CD4. After the presentation of an antigen connected with an MHC molecule the T helper cells are the ones starting to differentiate into the effector cells. Alternatively, the T helper cells can also differentiate into T memory cells which are responsible for the long-term immunity obtained against many pathogens.

Cytotoxic T cells:  The are part of the effector cells and  are recognized by their surface glycoprotein called CD8. Their utmost importance job is to monitor the body’s cells and kill the ones that present an antigen (always bonded with and MHC molecule I). For instance, such cells can be cells infected with a various, *cancer cells and a foreign tissue from a transplanted organ. 

Regulatory T cells:  They are identified by the presence of both CD4 and CD25 molecules in their cell membrane. However, Treg cells suppress immune responses, they basically are negative regulators of the immune system. It has been claimed that some members of the Treg cell subpopulation may be ancestors of the memory cells.

 

B lymphocytes mature in the bone marrow, and they compose and express some membranes molecules called antibodies or immunoglobulins (membrane bound immunoglobulins). These cells have receptors on their surface membrane called BCR and they are able to bind with antigens without the presence of MHC molecules.

 When a B lymphocyte cell interacts with an antigen for the first time, the cells start to get divided very quickly. It starts to differentiate into B effector cells which are called plasma cells and memory B cells. Memory B cells have a longer lifespan than B virgin cells and express the same membrane immunoglobulins as their parent cell. In addition, Plasma cells produce immunoglobulins in secretory form and have little or no membrane immunoglobulins. As a matter of fact, they are in the final stage of maturation and do not divide furthermore. However, they die within 1 or 2 weeks.

 

Nature killers (NK) cells are large granular lymphocytes and appear to have the ability of expressing cytotoxic activities against cancer cells and some virus infected cells. Nevertheless, it has been indicated that they do not contain receptors nor immunoglobulins. At the same time, an NK cell has receptors that allow the recognition of abnormalities, like the decrease of the expression of MHC class I molecules or the appearance of an unusual expression pattern of surface antigens, by some cancerous and virus-infected cells.

Some cancer cells express molecules that are foreign to our body. As a result, the immune system, triggers a respond by producing antibodies. These antibodies are called anti-cancerous (or anti-viral in case of virus-infected cells) antibodies that bind with the target cells. The NK cells, express a membrane receptor called CD16 which is designed for a specific region of the antibody molecule, and has the ability to bind to these antibodies  causing the destruction of target cells. This is known as Antibody-Dependent Cell-mediated Cytotoxicity (ADCC).

Sources :

Kuby immunology

 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 :