Mutation and Disease Association

Thrombocytopenia with absent radius (TAR)

The Bcl-2 protein can cause different types of mutations that can be vital to the survival of the organism in which the mutation occurs. In TAR, the deletion in chromosome 1 can lead to a disease called Thrombocytopenia. Thrombocytopenia is low blood platelet levels that can cause blood in urine and stool, rashes and uncontrollable bleeding after cuts (39). Upon deletion of q21.1, the RBM8A gene is deleted along with other genes. This deletion prevents TAR patients from having the CD34+ cells will be unable to differentiate into megakaryocytes. Although the details of the CD41+ cells in the apoptosis pathway are yet to be known as of 2016, it is known that immature CD41+ cell are involved in apoptosis. (37)

Severe congenital neutropenia (SCN)

The mutation that leads to SCN can lead to diseases such as neutropenia and infrequently AML (Acute Myeloid Leukemia . This genetic mutation defects mainly ELANE, GFI1, HAX1, G6PC3 genes. Myeloid differentiation during apoptosis is caused by different pathways which ultimately lead to genetic defects. This principle can be applied when the mutation cause deregulation of calcium homeostasis, one of the major functions of the BCL2 gene. The mutated HAX1 gene will cause the deregulation, following, the HAX1 gene will inhibit apoptosis. (37)

Renal Cell Carcinomas (RCC)

An acquired disease, RCC is caused by the mutation that blocks differentiation in apoptosis. Dysplastic bone marrow cells and ineffetive hematopoiesis are both casues of the mutation as they are are associatid with bone marrow faliure. Bone marrow failure is a result of increased p53 levels and expansion of premalignant cells. BCL2 expression is decreased as a result of the mutation as well as Bcl-2 associated proteins. (37)

Dyskeratosis congenita (DC)

Genetic disease, Dyskeratosis Congenita (DC) is a premature telomere shortening caused by mutation. The telomere shortening occurs on the gene that is originally used to cause elongation,lengthening of the telomere, and maintenance to the gene. Upon the shorteing, the p53, a tumor protein which usually prevents tumors is now activated, this prevents the cell cycle by inhibiting it and apoptosis. Bcl-2 is regulated by p53. PUMA, NOXA and BAX are all associated proteins to the Bcl-2. Studies on mice have shown this mutation causes pancytopenia, a deficiency in the blood cells, and the possibility of myelodysplastic syndrome (MDS) as well as secondary AML, another form of lymphoma. In the mice PUMA-mediated apoptosis causes prolonged lifespan. (37)

Lymphoma

There are different lymphomas associated with BCL2 mutations. Amongst those disease caused mutations, Follicular Lymphoma (FL) and Burkitt lymphoma are amonst the most common caused lymphomas. (37)

Follicular Lymphoma (37) is caused by a mutation that causes translocation of chromosome t(14;18) to (q32;q21). This mutation allows for extensive lymphoproliferation (38) which is the bodys response to a weak immune system and it causes the body to increase the quanitity of lymphocytes. If left untreated, the risk of further more aggressive lymphoma will be prevalent. The BCL-2 involvement in this mutation is over-expression and tumorigenesis. In the case of the extensive lymophoproliferation, research shows that lymphoproliferation is associated with higher risk of further transformations. Fortunately, translocation t(14;18) to (q32;q21) will not always cause the cancer. (37)

Burkitt Lymphoma (37) is caused by recurrent mutations in the MYC gene. The MYC gene is a regulator which codes for transcription factors while also playing a role in apoptosis(44) . A mutation of the MYC gene t(8;14)(q24;q32), causes the MYC gene to activate. Activation causes cellular apopotsosis at an incredibly high rate. Due to the high levels of apoptotic cells, Burkitt lymphoma is known for its "starry sky" appearance under a microscope. BCL-2 can be associated with BH3-only protein which are pro-apoptotic proteins, such as Puma, Bim, Bmf, and Bad. They are involved in mediation of the MYC gene's induced apoptosis. In the case of frequent extensive lymphoproliferation and frequent anemia, thrombocytopenia can occur. Thrombocytopenia is low blood pallet count (39), which comes with symptoms such as blood in urine and stool, excessive bleeding after a cut and rashes (39). On a physiological level, this is caused by the inhibition of apoptosis. The inhibition leads to an increase in MYC gene driven lympoma-genesis therefor causing the loss of Bcl-xL. (37)

There are different lymphomas associated with BCL2 mutations. Amongst those disease caused mutations, Follicular Lymphoma (FL) and Burkitt Lymphoma are amongst the most common caused lymphomas that are involved in the BCL2 mutation (37). Burkitt Lymphoma arises from a mutation in the MYC gene. This disease is not inherited, rather it is acquired. Its caused by recurrent mutations in the MYC gene (44). The MYC gene is a regulator which codes for transcription factors while also playing a role in apoptosis. A mutation of the MYC gene t(8;14)(q24;q32), causes the MYC gene to activate (37). Activation causes cellular apoptosis at incredibly high rate. Due to the high levels of apoptotic cells in the cell, Burkitt lymphoma is known for its "starry sky" appearance under a microscope. (37)

BCL-2 can be associated with BH3-only protein which are pro-apopotoic proteins, such as Puma, Bim, Bmf, and Bad. They are involved in mediation of the MYC (gene) induced apoptosis. In the case of frequent extensive lymphoproliferation and frequent anemia, thrombocytopenia can occur. Thrombocytopenia is low blood pallet count (39), which comes with symptoms such as blood in urine and stool, excessive bleeding after a cut and rashes. On a physiological level, this is caused by the inhibition of apoptosis. The inhibition leads to an increase in MYC gene driven lympomagenesis therefor causing the loss of Bcl-xL. In the figure attached below, the pathway of Burkitt lymphoma is displayed, among the pathways, proliferation, growth and survival are all. MYC gene acts as an instructor to antibodies in the body, as they lose their function and are limited to the lymphoma cells (40).

Burkitt Lymphoma is associated with tropical Africa as it is known as an 'African children cancer', in fact studies show that African children do make up about 30-50% of the Burkitt lymphoma cases but it's not exclusive to Africans (40) .

MYC gene sustains about 70% of mutations in Burkitt Lymphoma that are effecting transactivation of the Bcl-2 family (40). According to the research, MYC is so commonly mutated because of its overexpression in the cells induced by apoptotic pathways. Therefor explaining the mechanism. Some mutations caused an increase in protein stability. In the case of CCND3 the protein stability will increased (40).

Treatments

Some therapeutic regimens are available, most commonly used is intensive chemotherapy (40). Chemotherapy in patients with Burkitt Lymphoma are not very responsive to the therapeutic implication as chemotherapy is ideal in younger patients due to its higher success rate with less of a chance of relapse in patients (40) . The Chemotherapy suppresses ones immune system, and bone marrow. The significance of bone marrow depletion is blood is produced within the bone marrow as well as stem cells that help in regeneration of ones cells. Other treatments include oncogenic activation of cyclin D3. The activation has shown promising results, while unfortunately the mechanism for this treatment is unknown. The scientists believe that CDK-6 and Cyclin D3 pair to block the Burkitt Lymphoma cell-cell progression, ultimately isolating the cancer (40).

Venetoclax (41,42), a Bcl-2 inhibitory drug being one of the drugs. Venetoclax was the first FDA approved Bcl-2 inhibitor drug (43). The drug acts as a BH3 and is able to only inhibit Bcl-2 function without sacrificing the function of the vital family members of Bcl-2 (41,42). A mutation is caused there are also immunotherapies, immune check point inhibitors, antigen receptor T cells and bi specific antibodies that all play a role in the latest research and clinical trials tackling lymphoma head on. B cell receptor inhibitors, SYK inhibitors, BTK inhibitors, PI3K, BCl-2 inhibitors, Navitoclax, Venetoclax, JAK/STAT pathway inhibitors, Immunomodulatoy drug, Immunotherapy, Chimeric an antigen receptors T cells inhibitor, Bite and bispecific antibodies, antibody-drug conjugates, epigenetic modifying drugs, and EZH2 inhibitors (41)

Without treatment, Burkitt Lymphoma is fatal and remission may be expected for those patients who receive therapy (45).