Cancer Immunology | Lymphoid Tumors

[00:00] Let's see what are lymphoid tumors. The uncontrolled division of lymphocytes leads to the condition called lymphoid tumors. These are the malignancies that affect the adaptive immune system. As lymphocytes are the main components of adaptive immune system, they originate from a single lymphocyte or plasma cell.

[00:20] Each cell of the malignant population has undergone identical immune receptor, gene rearrangements and expresses identical immunoglobulin, or T, cell receptor, TCR, molecules. This identical nature of the cells is referred to as monoclonality. The cellular origin of these

[00:40] lymphoid malignancies can be T cells, pre B cells, mature B cells, and plasma cells. Here the characteristics of each type of tumor are different and can be dictated by the biology of the originating cells, some common lymphoid malignancies.

[01:00] their cellular origin and characteristics are listed here.

[01:20] of disease that can invade in other tissues, for example brain tissues, and its treatment mostly required replacement of bone marrow. Untreated all can kill within week of diagnosis. Another lymphoid malignancy is chronic lymphocytic leukemia, CLL. It is derived from

[01:40] the mature B cells. CLL is common in elders and it may not be much aggressive or we can say it is a non-aggressive lymphoid malignancy. In CLL, malignant cells are present in blood, so they can invade other tissues but takes much time. Next you will hear the term lymphoma many times

[02:00] this video. It is a lymphatic malignancy that involve mature B cells, like in CLL. But unlike CLL, it is frequently associated with EVV infection together with some genetic alterations, and it tends to cause solid lesions that often begin in lymph nodes.

[02:20] We can say, in CLL malignant mature B cells are present in blood, while in lymphoma, malignant mature B cells are present in lymph nodes and sometimes other tissues. Next common lymphoid malignancy is known as multiple myeloma. This condition is derived by malignant mature B cells.

[02:40] plasma cells. In myeloma, the clone of malignant plasma cells produces monoclonal immunoblobulin that can be found in blood or in urine samples. So can be detected by the presence of monoclonal antibodies. This malignancy is relatively common in elderly.

[03:00] T-cell malignancy that is a rare one among all other lymphatic malignancies, and may be associated with a particular viral infection named as HCLV1. This condition can behave either as leukemia with blood involvement or as a lymphoma with solid tissues involvement.

[03:20] it. After getting brief concept about certain lymphatic malignancies, let's look at the possible causes of these malignancies. Because cells from lymphoid malignancies are easy to remove and grow in vitro, much is known about how they arise. And this is usually the result of oncogenes activation

[03:40] by chromosomal translocations, or the effects of pathogens. Let's see how these reasons leads to oncogenesis of lymphoid cells. Starting with chromosomal translocations, some genetic alterations in DNA can cause cancer, especially when these alterations are not available.

[04:00] patients occur in proto oncogenes that are a group of genes involved in normal cell growth. The mutation in these genes make them oncogenes that are the cancer causing genes. Also some alterations in tumor suppressor genes can cause cancer as tumor suppressor genes are.

[04:20] actually group of genes that regulate cell division and replication. As we know, the uncontrolled cell growth can lead to cancer. And these tumor suppressor genes prevents it. So these are also called as anti-oncogenes. But when these genes get mutated, there is loss or reduction in their function.

[04:40] and thus it can lead to tumor formation. Other than these, genetic alterations in DNA repair genes can also cause cancer. As name shows, these DNA repair genes work in a diverse set of pathways and ultimately protects and repair damaged DNA.

[05:00] But if there will be alterations, it won't be able to work efficiently, leading to cancer formation. Similarly, DNA alterations in other genes can also lead to tumor formation. Examples of such DNA alterations include deletions, inversions, and chromosomal trans-

[05:20] translocations. Where deletions is a type of gene mutation in which a part of DNA molecule is left behind or is not copied during DNA replication. Inversions are the chromosomal rearrangement in which segment of a chromosome is reversed end to end.

[05:40] And the last one is chromosomal translocations that are actually translocations of chromosomal gene segments, and it is generally considered as the primary cause for many cancers including lymphomas and leukemias. So here we will discuss chromosomal translocations in detail.

[06:00] Let's see what is it? In a chromosomal translocation, a segment of genes from one chromosome is transferred to a non-homologous chromosome, or a segment is transferred to a new site on the same chromosome. So in this way, translocation placed genes in a new linkage relationship, and generally-

[06:20] generate chromosomes with abnormal pairing partners. When this genetic linkage with considerable strength is established between them, two different chromosomes behaved as if they were physically linked. This chromosomal translocation may usually occur. During immune receptor gene recombination where chromosomal

[06:40] may not be correctly repaired. Also in B-cells, chromosomal brakes can occur during class switching as well. We have explained this class switching very well in our previous video under the title Antibody Diversification and Synthesis. So if you want to know more about it, watch it there.

[07:00] Now, this chromosomal translocation often has lethal consequences for the lymphocyte. However, some rare chromosomal translocations have positive effects on cell survival, but is a very rare occasion. But normally these translocations are associated with negative consequences, such

[07:20] such as infertility and cancer, etc. The exact molecular mechanism of chromosomal translocations is not fully understood. But studies suggest that development of malignant tumors by chromosomal translocation may involve. The change in original location of proto-oncogenes that are

[07:40] normally required for cell growth. But change in their vocation may convert them into oncogenes. Well, this activation of oncogenes by chromosomal translocations usually involved two mechanisms. That are placement of proto-oncogenes near regulatory elements, and

[08:00] formation of fusion oncoprotein. Let's try to understand these mechanisms. Here in first mechanism, a promoter or regulatory sequence of gene A, and a coding exone or coding sequence of gene B. Both these gene segments are located on two different chromosomes.

[08:20] Now, if translocation occur between them, then it will bring that coding sequence of gene B in close proximity to the regulatory sequence of gene A. It can be better described. From the first translocation observed of this kind, it was observed in Birkitz lymphoma, a lymphoma involving

[08:40] B lymphocytes, where translocation was observed between chromosome number 8 and chromosome 14. This particular translocation places the MYC, proto-oncogene, from chromosome 8 to the proximity of immunoglobulin-heavy chain gene, i.g. it.

[09:00] Promoter on chromosome 14.

[09:20] leading to overcell proliferation as it altered expression of genes. And so it leads to serious lymphomas, like Birkett's lymphoma in this case. Now let's understand the second mechanism, that is, formation of fusion oncoprotein. Some translocations fuse the coding sequences of two genes

[09:40] together, for example of gene A and gene B. This fusion then generate potent oncogenes. That is the group of genes that have capacity to generate tumor cells. Here, its example from historic studies is the Philadelphia chromosome, which was initially identified as a minute or a new

[10:00] unusually small. Chromosulmon patients with chronic myelogenous leukemia, CML. Subsequent molecular analysis revealed that the translocation fused the coding sequence of the BCR, breakpoint cluster region, gene on chromosome 22. With the coding sequence

[10:20] of ABL gene on chromosome 9, and the product of this reciprocal transulcation is placed on the arms of Philadelphia chromosome. Now the fused protein formed is the BCR AVL fusion protein. This fusion protein makes an oncogenic sequence that constitutively

[10:40] activates signaling pathway involved in cell growth and proliferation. In normal lymphocytes, proliferation is always balanced by apoptosis. But this activated BCR-ABL fusion protein protects against apoptosis, which allows unrestrained proliferation of lymphocytes.

[11:00] Knowledge of this particular breakpoint has led to a successful treatment for CNL because investigators were able to use the sequence information to overexpress and crystallize the BCR-ABL protein, which in turn led to the development of drugs that inhibit this protein's activity.

[11:20] Hundreds of different translocations have been linked to cancer, and still scientists are working to identify new molecular rearrangements that may occur in cancer so that effective and efficient treatment can be suggested against this devastating disease. Oncogene translocations are more likely to occur after exposure to radiation.

[11:40] Now, other than chromosomal translocation, other reason of lymphoid tumors can be pathogens. Let's see what are those pathogens that are known for causing lymphoid tumors. Firstly comes herposvirus family members and retroviruses. They both infect cells without killing them. It is in the end

[12:00] interest of viruses to stimulate uncontrolled growth of these infected cells. Next are Epstein-Barr viruses, EBV. EBV is known for causing infectious lymphomas and carcinomas. EBV does not convert the cellular machinery to virus production and destruction of the cell.

[12:20] Instead, EBV immortalizes cells by producing proteins that drive B-cell proliferation and inhibit aheptosis. EBV proteins also help infected cells evade the immune response by blocking antigen presentation. All these factors promote the growth of a malignant B-cell population.

[12:40] circulation. This uncontrolled division then leads to lymphomas. Other than EBV, helicobacter pylori is another organism that can contribute to the development of lymphoma. A-pylori is a bacterium that triggers chronic inflammation in the stomach. This commonly causes stomach ulcers.

[13:00] More rarely, the inflammation caused by H. pylori causes lymphomas to arise in the associated mucosa-associated lymphoid tissue mald. Importantly, treatment of the H. pylori infection can lead to the lymphoma going into remission.

[13:20] In addition, HTLV1 is also another type of virus that can cause lymphomas. Particularly, it is responsible for T cell malignancy that is rare. But when it occurs, it is often caused by human T lymphotrophic virus 1. This retrovirus encodes tax protein, which

[13:40] has effects similar to interleukin-2 that acts as T cell growth factor, and thus promoted T cell growth. This HClV1 is rare in developed world, but still exists in developing world. So this was all about tumors that involve immune cells that are lymphocytes.

[14:00] Until now, how cells of the adaptive immune system may give rise to tumors has already been discussed.

[14:20] therapy would offer hope to patients with cancer, most types of which remain incurable. We will discuss immunotherapies in detail later in this video. But to understand it better, it is important to know how malignant cells may become antigenic, or, in other words, how they express tumor antigens.

[14:40] learn about it in next section.