S C I E N C E

 As mentioned above, myelodysplastic syndromes is a term referring to a group of malignant tumors. This means that all the “crew members” this group is made from, have some common characteristics and some differences. Let’s take for instance one person who changes his clothing style every week. He remains the same person but with a different appearance, however   his main features like his genetic trait and face features remain the same. Likewise, this cancer can appear in different forms. The first scientific classification of these different forms was called FAB classification. Later, question marks and doubts about the heterogeneity and various distinctions between the subcategories concerning their association with other syndromes started emerging. For this reason, another distinction eventually prevailed, the WHO assortment. In this article, I will refer to all the different ways a myelodysplastic syndrome can appear.

 

Refractory anemia (RA)
 Refractory anemia with ringed sideroblasts (RARS)

In the peripheral blood and the bone marrow, we can observe the same findings as with the RA subtype, with only difference laying in the bone marrow where the ringed sideroblasts go beyond the 15%. 

 Ringed sideroblasts appear around the nucleus. They are a result of the disrupted iron intake. This disturbance leads to the existence of increased iron in the cell and in the mitochondria. The mitochondria filled with the extra iron, move around the nucleus and create a ring-shaped format. 

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In the blood, there is a general decrease of the mature blood cells: reduction of neutrophils and of the platelets number. Also, blasts can be seen in the peripheral but less than 5%. In the bone marrow, we have dysplasia in one cell row, or can even be found in more than many cells rows. The blasts can appear from 5-9%. 

 Myelodysplastic syndromes is a term we use for a wide group of malignant diseases of the hematopoietic tissue that can differ from each other but all have some main common characteristics : All of the myelodysplastic syndromes are diseases of the hematopoietic tissue and they are caused by a clonic disorder of the multipotent stem cell. Normally,  the stem cells when they differentiate they “give” one stable line of undifferentiated cells and a line of cells that will eventually evolve into a type of blood cells. Multipotent stem cells have a very high capacity of self -renewal and they have the ability to differentiate into different cell types in an adult. So basically, the first adult hematopoietic cells can start differentiating out of the normal line, causing different types of syndromes.

Let’s take a look now, in some other common features these syndrome have :

There is ineffective hematopoiesis, we see Cytopenia so there aren’t being produced enough cells for some blood types, the bone marrow is full of cells, the Cells have various morphological disorders, we have different percentage of blasts in the bone morrow in comparison with the percentage of  a normal person , we see chromosomal abnormalities that have not been inherited and lastly there are some myelodysplastic cases that will eventually progress in becoming acute melogenic leukemia.  (Connection between Myelodysplastic syndromes and AML). It is considered that  as the person grows older, so does the risk of developing the disease grows. Further, myelodysplastic syndromes can be developed as a primary disease, but they can also appear as secondary as a result of some medications.

How does a MDS develop?

One stem cell, a multipotent hematopoietic stem cell, ends up with damaged genetic material that is irreversible.  This damage that is often found lies in transcription factors, in histones or in DNA methylation. There is also the  Methylation of P15 (INK4B) , a tumor suppressor gene that is found in 30-50% of cases of MDS and seems to be related to the DNA methylation .  In essence it is an epigenetic glitch, the sequence of genes does not change but the expression gets altered.

 These damages make the cell more powerful and advantageous  over the other normal stem cells. As it starts multiplying and generating more copies of itself, the bone marrow eventually becomes flooded with this particular cell and its daughter cells. In addition, our mutated cell can change the expression of MHC molecules on its surface so that it can avoid an immune response, getting away from our immune system.

Further, this “problematic” cell will cause a lot of changes to our cell mechanisms. For example, the metabolic pathways of stimulus treatment get altered so they will not be affected by apoptotic factors, while the normal cells are quite sensitive and responsive to them. The result is, this cell and its progeny will prevail over other normal cells. Equally important is to note that, the cancerous stem cells create changes to growth factors and to the RAS molecule, which is an intracellular signal molecule that provokes cell proliferation. Basically, mutations in this molecule promote carcinogenesis.

The MDS PARADOX

The bone marrow of a person with MDS is filled with blasts and stem cells and cells in general with cytopenia in peripheral blood while at the same time there is an increased proliferation and apoptosis in hematopoietic cells.

Patients who show a High rate of stem cell apoptosis often  have  "good" prognosis of the syndrome. Basically, it is very important for the cells to not lose their ability of apoptosis.

Apoptosis is the programmed cell death. In order for a cell to do apoptosis, it needs to consume energy  and develop morphological characteristics such as chromatin contraction, oligomeric changes in DNA, nuclear envelope fragmentation and cellular condensation. Basically the cell is cut down into much smaller sections and these sections will later be phagocytosed. It is a way of "silent suicide" without disturbing the cell environment.

Apoptosis is very important of a healthy organism because it keeps the number of tissue cells at the right level. All cells must have the ability to go through apoptosis. It is crucial not the confuse apoptosis with cell necrosis, which is a cell destruction which isn’t silent and will disturb the surrounding environment.

So, MDS cells do have a high ability to apoptosise. There an increasement of a tumor necrosis factor , TnF-α ,  which is basically a  cytotoxic factor that causes cancer cell to terminate and has been found to rise in MDS/

Additional, there is an Increased expression of the Fas and Fas-Ligand (FasL) gene on CD34+. Those are , signals that trigger apoptosis.

Also, there has been found an augmentation of c-myc/bcl-2  or bax/bad versus bcl-2/bcl-x , basically a rise in the expression of apoptotic genes in comparison to anti apoptotic  genes.

So in the end, what can be seen, is that those syndromes have the benefit of a high level of apoptosis which can lead to a good prognosis of the disease. The paradox however remains, due to fact that we still see proliferation and apoptosis.

The reason why hematopoiesis is not properly taking place is not fully understood, since there is dilemma emerging. It is not clear, if the problem arises exclusively because of the mutated - problematic but more aggressive and stronger stem cells or if the T lymphocytes unknowingly help the whole process. There has been found that T lymphocytes can suppress BFU-E colonies which are precursors of red and granulocyte cell line colonies as well as CD8+ lymphocytes are able to suspend the evolution of CFU-GM colonies. Another essential element in the whole case, seems to be that patients who were given immunosuppressive drugs have shown a better response than other patients who got different kind of treatments.

But how do lymphocytes help cancer cells?

One  mechanism that has been suggested is that T-lymphocytes participate in the process and in the development  of MDS. In detail, they help the mutated clone to avoid the immune system.

The T-cells are the first ones to recognize the cancerous stem cells through MHC molecules (molecules of our own cells that recognize whether a cell is self-contained or foreign). Since the T cells recognize the problematic cell   they start to proliferate and to secrete cytokines in order to suppress hematopoiesis, in order to this specific mutated cell to not be cloned.

 But at the same time they help the cancer cell to secrete, produce and express proteins  which will prevent the immune system cells to realize which is the cancer cell and as a result the mutated stem cell will be able to “hide” from the immune response. This phenomenon does not seem so strange anymore because it has been found that general cancer cells  have the ability to use elements of the body against itself as well as using molecules of the body's defense against normal cells.

Cancer cells grow in the bone marrow in a specific microenvironment which includes:

Cytokines

 A number of cytokines, IL-6, IL-8, SCF, EPO, TGF-β, GM-CSF, TNF-α,  were measured in the serum and marrow of patients with MDS , with unclear and often conflicting results.

There is an increased secretion TNF-α by macrophages and T lymphocytes in the marrow. This secretion was associated with a high expression of the Fas antigen, a pathway that also leads to apoptosis. Basically the FAS binds to FAS-L which will active some proteins called prokaspases and caspases which are proteases that lead to cell death , by CD34 + cells.

In short, in the environment of bone marrow T lymphocytes produce cytokines cytokines that will prevent hematopoiesis by enabling the apoptosis.  In the same time, those cytokines are perceived by the cancer cells, which will produce other molecules that will make them invisible to the immune system. And that’s the only explanation there is for one part of this paradox phenomenon : This type of cancer appears with high abundance of apoptosis which can be a good thing but also this the reason why the cancer cells are able to get away from the immune system.  Due to this fact, it is very difficult for a cure to be found, since the scientists can not predict how the disease will evolve while the cancer cells try to “fool” our system.

 In myelodysplastic syndromes, an augmentation in angiogenesis can be seen

Angiogenesis is a complex process that takes part in the formation and creation of cancer. The density of new blood vessels is higher in MDS in comparison with other types of Leukemia. In fact, the aggressiveness of a cancer types goes hand with more intense angiogenesis. This is not a surprise, since the main role of cancer cells is to find a way to get into the blood circulation. As it is expected, high levels of VEGF appear, which is a vascular endothelial growth factor that helps in angiogenesis and increases the vascular permeability. Therefore, the enlargement of angiogenesis and VEGF is often a sign of a bad prediction of the disease.

 

Next, I am going to present some possible reason that are considered to be the causes of those syndromes by the research community:

As mentioned above, myelodysplastic syndromes can appear due to borht primary and secondary causes. However, the majority of these diseases are primary, they appear on their own, without being the result of a drug that has already been given to the person.

Primary Myelodysplastic syndromes can be caused because of:  

Heredity  

Familial monosomy 7 is the lack of the long arm of chromosome 7

Trisomy 8 mosaicism:  This is disorder in the mitotic  separation of chromosomes. Depending on when this disorder occurs either in the first division, the cell appears to be mosomal or in the second where we have trisomy. The person can also have  half normal karyotype, ¼ trisomy, ¼ monosomy.

Kostmann, Schwachman-Diamond

Fanconi anemia, Bloom syndrome

Neurofibromatosis 1

Embryonal dysgenesis (del12p)

Moreover, cytogenetic lesions can be found, with 70% of them occurring in primary MDSL while 90% in secondary MDS. Those abnormalities mainly have to do with  chromosome segment losses .

The Karyotype can show some cytogenetic lesions. Applying fluorescent in situ is a way in which we can mark certain areas to see if there are permutations between chromosomes, changes between the genetic material of chromosomes.

Smoking

Myelodysplastic syndromes relate with the duration of smoking. Consequently, a person is actually in high risk of developing MDS 15 years even after they stop smoking.

 

 Secondary causes of myelodysplastic syndromes:

Ionizing radiation

Patients who have been radiated in the pelvis and spine, people who have been near atomic explosions, or even in near countries, patients who have received radioactive phosphorus. It is important to be noted that someone can develop MDS 17 years after the radiation.

 

Benzene or benzene

The exposure to gasoline and other petroleum products from 1-15 years can increase the risk of developing MDS.

 chemotherapeutic drugs

The alkylating agents chlorambucil, cyclophosphamide, melphalan, nitrosures, busulfan, procarbazine can be administered to a patient and it is considered that he may develop a myelodysplastic syndrome 5 to 7 years after the chemotherapy with the maximum risk between the 2ed and the 5^th year. In essence, these agents have a cytotoxic effect. Their action is related to their ability to form strong covalent bonds with DNA bases and interfere with the normal functioning of DNA. Τhey can act non-specifically and create "cross bridges" so that the process of replication or transcription can not be done properly. They can also act specifically which in some cases results in mutations while the cell is trying to correct these changes through repair enzymes often ends up creating  DNA fragments because it can not deal with the mutations or mistakenly bind the bases. So ultimately, the way Alkylating agents act is either by blocking transcription and replication, or by acting directly on mutations, or by leading to DNA fragments

It is important to be noted that those agents, are often prescribed to cancer patients in cancer treatment programs and their main goal is to keep the cell from reproducing since it damages its DNA. So basically, those drugs are essential for a cancer patient and they are important to the survival rate. However, in some cases, they can contribute to further damage of normal stem cells and end up mutating them, creating a new cancer disease for the patient. A vicious circle which is created and harnessed by cancer.

 Comparing Smoking – benzene-chemotherapy drugs:

According to recent studies there are evidence showing that MDS increases more among smokers due to the presence of polycyclic hydrocarbons (benzene) and many other carcinogens in tobacco. Also, people who develop MDS after being affected by benzene, have a similar disease growth to those who develop the syndrome after chemotherapy with alkylating agents. The reason why is that petroleum products have a similar molecular acting as the alkylating agents have. In the end, smoking can be compared with inhaling benzene and taking a heavy chemotherapeutic drug. 

Cell morphology in MDS

Τhere is a disruption in all cell lines.

Dyserythropoiesis

In peripheral blood, we can see dimorphism, double population of red blood cells, Anisocytosis – multicellularity which means many types of morphological changes in erythrocytes. Ovarian macrocytes, elliptocytes, tear cells, erythroblasts with megaloblastic characteristics, like a  change in the proportion of nucleus to cytoplasm, insufficient hemoglobinization of erythrocytes.  All of these indicate a disorder in the maturity of red blood cells, with genetic material residues.

In the bone marrow we can see erythroblasts nucleus with more lobes, or karyorixia, where the shrunken nucleus breaks down and disappears completely. In addition, there is a change in the ratio of nucleus to the cytoplasm, there are Ring iron blasts where rings appear around the nucleus. This is caused by a disturbance in the intake of iron, the cell takes up more iron in the mitochondria and as a result, the mitochondria go around the nucleus and create this ring.

 

Disgranulopoiesis

In Peripheral blood we can see neutropenia, reduced cytoplasm granulation ,  myeloperoxidase negative, a reduction In the nucleus lobes with an increased density  and thickening of the chromatic (pseudo-Pelger-Huet abnormality). An over segmentation of the nucleus is seen, as well as basophilia in the perimeter of the cytoplasm. In some cases there is an  increased granulation of the cytoplasm with large azurophilic granules instead of the usual ones (pseudo Chediac Higashi). Lastly, we can see blasts with or without Auer sticks. (Note that blasts shouldn’t be seen in the blood)

In the bone marrow, we can see hyperplasia, with the premature forms of the granular cell line being dominant while suffering from maturity both from the nucleus and the cytoplasm.

 Dismegakaryopoiesis

In the Peripheral blood we see thrombocytopenia, Hypocranial or non-granular platelets ( basically platelets with little or absent granules), Giant platelets,  Pathological functioning platelets. Also, megakaryocyte fragments will appear. Note that, megakaryocytes do not normally exist in the peripheral blood , only in the bone marrow and from them , the platelets will be created , and these are the ones we are supposed to see in the blood.

In the bone Marrow we can see micromegakaryocytes (<20μm). Normally they are quite large while in the MDS they will appear quite small. They will have  multiple small nuclei and with less granules . A mononuclear form with a small round eccentric nucleus with a cell diameter of less than 30 μm is associated with the cytogenetic abnormality 5q.