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.

      https://imagebank.hematology.org/image/1456/blast-crisis-of-chronic-myelogenous-leukemia--4?     type=upload

                                             Blast crisis, the blasts in the peripheral blood

              https://imagebank.hematology.org/image/2312/blast-crisis-of-cml--1?type=upload

Chronic basophilic leukemia

This syndrome is extremely rare and has some changes for slow progress into acute leukemia and is considered a myeloproliferative illness as well as the previous two that have been mentioned. Chromosomal abnormalities have been detected such as the deletion of chromosome 20, deletion of chromosome 11, trisomy 9, chromosomal translocation (9:22). Also, a hyperplasia of the granulocytes has been noticed, while the bone marrow seems to be super cellular with an extreme increasement in myelocytes, basophils and a smaller rise of red blood cells and megakaryocytes. However, blasts and promyelocytes do not appear increased.

https://www.semanticscholar.org/paper/Diagnostic-Problems-in-Chronic-Basophilic-Leukemia-%C3%87ehreli/a649e5d8dc110a3a0fd284003aa9a31db2dd27bc