1. Cancer of the Immune System
Hi everyone, my name is Valente
-and my name is Jenny
-today we’ll be talking to you guys about cancer of the immune system
-so just earlier today we heard about how the immune system can protect us from cancer, and how there’s a complex interplay between the immune system and the development of cancer
-but our immune cells can also themselves develop cancer, and so today we’ll be introducing you guys to the different types of cancer in immune cells
Yun Jing (Jenny) Ma
Valente Shiu
PHM142 Fall 2019
Coordinator: Jeffrey Henderson

2. Cancer in Immune cells Leukemia Lymphoma Myeloma
Cancer cells are altered self cells that proliferate in an unregulated manner
Generally referred to as blood cancers or hematologic cancers
3 main types of blood cancer:
Leukemia
Lymphoma
Myeloma
-to quickly review, cancer cells as I’m sure we all know are altered self cells that have escaped normal growth regulating mechanisms, and as a result they proliferate in an unregulated manner
-the terms blood cancer or hematologic cancer are used to broadly refer to the different cancers that can occur in immune cells
-3 main types of blood cancer: leukemia, lymphoma, and myeloma

3. -leukemia is cancer that originates in the blood and bone marrow, and it’s caused by the overproduction of abnormal white blood cells
-lymphoma is cancer that develops in the lymphatic system from lymphocytes
-myeloma is cancer that begins in the plasma cells of the bone marrow (recall are the antibody-producing B cells)

4. 10% Canadian Cancer Statistics 2019 (Canadian Cancer Society)
-leukemia lymphoma and myeloma are very important types of cancer
-this image shows the percent distribution of new cancer cases in Canada in 2019
-the ones highlighted by the red boxes are all blood cancers, and in total they make up about 10% of all new cancer cases in Canada

5. Leukemia
Malignant proliferation of hematopoietic stem cell/progenitor cells
Involves cells of lymphoid or myeloid lineages
4 main types of leukemia:
Acute lymphoblastic leukemia (ALL)
Chronic lymphocytic leukemia (CLL)
Acute myeloid leukemia (AML)
Chronic myeloid leukemia (CML)
-we’re first going to focus in on leukemia
-leukemias involve malignant proliferation of hematopoietic stem cells or progenitor cells, so in other words these are immature cells that have arrested differentiation at a precursor stage
-broadly, leukemias are classified into 4 main types: ALL, AML, CLL CML
-in general the acute leukemias progress and worsen very quickly if they are not treated, while the chronic forms progress slowly
-ALL and CLL affect the lymphoid lineage while AML and CML affect the myeloid lineage

6. Acute lymphoblastic leukemia (ALL)
Occurs more often in children
80% of all cancers in young children ages 2-6
Affects either B cell (mostly) or T cell lineage
Associated with chromosomal abnormalities or point mutations
-ALL is largely a disease of children and young people, it is uncommon over the age of 20 years
-as its name suggests, this form of leukemia occurs in the lymphoid lineage and affects either B or T cells
 although most of the time ALL arises in the B cell lineage
-ALL is associated with chromosomal abnormalities or point mutations
-these mutations often occur in transcription factors or proteins associated with lymphocyte development, lineage commitment, and differentiation
-and so mutation of these genes result in arrested differentiation at a precursor stage, which means that these cells retain stem-cell like properties and undergo uncontrolled self-renewal
-as we can see there are lots of different gene mutations that can contribute to ALL
-as an example, PAX5 highlighted on the chart is a very important transcription factor needed for B cell lineage commitment
-when PAX5 gets mutated, B cells fail to complete development and they arrest at a precursor stage

7. Acute lymphoblastic leukemia (ALL)
Risk factors:
Exposure to x-rays before birth
Exposure to radiation
Past treatment with chemotherapy
Having certain genetic conditions (Eg. Down Syndrome)
Acute lymphoblastic leukemia (ALL)
-some notable risk factors for ALL include exposure to x-rays before birth, exposure to radiation, past treatment with chemotherapy, and having certain genetic conditions (such as donw syndrome and several others)
-so these are all things that could possibly induce a chromosomal or point mutation early in life

8. Chronic lymphocytic leukemia (CLL)
Occur almost entirely in elderly patients
Slow progression
Mostly arises in B cell lineage (95%)
-from the graph you can see that ALL onset occurs primarily in childhood and adolescence while CLL onset occurs primarily in late adulthood and elderly patients
-another key difference between the two is that unlike ALL, CLL has very slow disease progression
-similar to ALL, CLL is caused by abnormal or arrested differentiation mostly in the B cell lineage

9. Acute myeloid leukemia (AML)
Occurs mostly in adults
Cancer of the myeloid lineage of cells
Associated with mutations that inhibit myeloid differentiation
-AML occurs mostly in adults, and it involves uncontrolled proliferation of precursor cells of the myeloid lineage
-AML is associated with many gene mutations that inhibit myeloid differentiation
-as an examples, point mutations in FLT3 occur in more than 50% of all AML cases
FYI: FLT3 is a receptor tyrosine kinase normally expressed by hematopoietic stem or progenitor cells and plays an important role in the early stages of myeloid cell development

10. Chronic myeloid leukemia (CML)
Usually occurs after age 60
95% of CML patients have a Philadelphia chromosome (BCR-ABL fusion gene)
-CML usually occurs after age 60
-CML is caused by a reciprocal translocation of genetic material between chromosome 9 and 22, which is illustrated in this diagram here
-this translocation fuses part of the ABL gene from chromosome 9 with part of the BCR gene from chromosome 22, creating an abnormal fusion gene called BCR-ABL1.
-this fusion chromosome is often referred to as the Philadelphia chromosome
-ABL gene is involved in many cellular processes, including cell proliferation, maturation, migration, and apoptosis
-the fusion gene BCR-ABL1 not only retains all the functions of ABL, but it becomes constitutively active and drives the cell to divide uncontrollably
-when this mutation occurs in myeloid progenitor cells, it gives rise to CML

11. Symptoms Leukemia Fever Infection Easy bruising or bleeding Anemia
Weakness and fatigue
Loss of appetite
Lymphadenopathy
Hepatosplenomegaly
Leukemia
-symptoms between different types of leukemia are similar
-common symptoms include fever, infections because a portion of your immune cells are compromised
-easy bruising or bleeding and anemia can occur due to the fact that overgrowth of the cancerous cells crowds out the other blood cell types and impairs their development, which can lead to a shortage of red blood cells and platelets
-you can also get weakness and fatigue, loss of appetite, lymphadenopathy and hepatosplenomegaly
FYI: lymphadenopathy and hepatosplenomegaly could be either due to increased infections or infiltration of these organs by the leukemic cells

12. Lymphoma
Malignant proliferation of lymphoid cells found in the lymph node or spleen
2 types: Hodgkin’s lymphoma and non-Hodgkin’s (NHL) lymphoma
-Malignant proliferation of lymphoid cells that reside in the lymph node or spleen
-most lymphomas result from defects in germinal center B cells, so these are mature B cells that have been activated by their antigen and go to the germinal centre to undergo affinity maturation and class switching
 so somewhere along the way during this process, the B cells become mutated and divide uncontrollably to form tumors in lymph nodes or the spleen
2 types: Hodgkin’s lymphoma and non-Hodgkin’s (NHL) lymphoma

13. Hodgkin’s Lymphoma Mostly affects young adults (under 30 years of age)
Hodgkin’s lymphoma occurs in germinal centre B cells
Binucleate Reed- Sternberg cells
Presents with painless lymphadenopathy
-Hodgkin’s lymphoma mostly affects young adults, often under 30 years of age
-it occurs in germinal centre B cells of lymph nodes and the spleen
-a hallmark of Hodgkin’s lymphoma is the appearance of binucleate Reed-Sternberg cells, which are neoplastic B cells
-these Reed-Sternberg cells are large, and have a very recognizable binuclei that resembles owl eyes
-in the image here, you can see the distinct size and appearance of the Reed-Sternberg cells compared with all the normal B cells surrounding it
-how or why they get this particular morphology remains unknown
-common symptom is painless lymphadenopathy, especially in the neck or mediastinal region
Hodgkin’s Lymphoma

14. Non-Hodgkin’s Lymphoma
Broad group of all lymphomas that do not have the typical histological features of Hodgkin’s disease
May be of either B (90%) or T cell (10%) origin
Symptoms similar to Hodgkin’s disease
Non-Hodgkin’s Lymphoma
-Non-Hodgkin’s lymphoma encompasses all lymphomas that do not have the typical histological features of Hodgkin’s disease, which means there are no appearances of Reed-Sternberg cells
-non-Hodgkin’s lymphoma can be of either B or T cell origin, although B cell origin is still much more common
-symptoms in Hodgkin’s and non-Hodgkin’s lymphoma are similar, which includes lymphadenopathy, weight loss, unexplained fever which are all fairly non-specific symptoms

15. Multiple Myeloma Median age of diagnosis is 65-70 years
Uncontrolled proliferation of clonal plasma cells
Produces abnormal antibodies known as M proteins
-myeloma, also known as multiple myeloma, is cancer involving Uncontrolled proliferation of clonal plasma cells
-to refresh your memory B cells, upon activation, can differentiate into plasma cells that produce antibodies
-this activation and differentiation occurs in the germinal centers, then the differentiated plasma cells migrate back to the bone marrow where they reside and continuously produce antibodies
-while normal plasma cells produce normal antibodies, myeloma cells produce dysfunction antibodies which are also referred to as M proteins
FYI: myeloma is called multiple myeloma because most people have multiple bone lesions when diagnosed, and this also coincides with multiple myeloma tumors in the bone marrow

16. Multiple Myeloma Signs & Symptoms
Bone pain
Fatigue
Weight loss
Infections
Hypercalcinemia
Impaired kidney function
Multiple Myeloma Signs & Symptoms
-one of the most common symptoms of multiple myeloma is bone pain, and this is because the myeloma cells form tumors within the bone and causes bone pain
-patients also experience fatigue and weight loss, and increased susceptibility to infections
-The presence of myeloma cells in the bone marrow increases bone breakdown and prevents the production of new bone cells, which results in release of calcium from bone into blood and causes hypercalcinemia
-lastly, patients eventually develop impaired kidney function, and this is partly due to the hypercalcinemia and due to accumulation and precipitation of dysfunctional antibodies

17. Hematopoietic stem cell transplant
Treatment Options
Chemotherapy
Radiation
Monoclonal antibody
Hematopoietic stem cell transplant
-conventional treatment for blood cancers can include combinations of chemotherapy, radiation, monoclonal antibodies, or hematopoietic stem cell transplantation
-in monoclonal antibody therapy, you can generate antibodies that target specific antigens expressed by the cancer cells and link the antibody to a cytotoxic drug, toxin, or radioisotype that will kill the cell one the antibody binds to it
-stem cell transplants are sometimes initiated after chemotherapy or radiation therapy to help restore the stem cells in the bone marrow because these often get damaged or destroyed throughout treatment
-there are a lot of factors that influence the treatment plan, including disease subtype, what type of cells are affected, cytogenetics, patient age, and disease stage
-however, survivors of blood cell cancers have an increased risk of subsequent cancers, likely because of the cellular damage caused by chemotherapy or radiation
-in general, ALL has excellent outcome in children, and a complete remission is achieved in 95% of children undergoing initial high-dose chemotherapy
-in the case of the chronic leukemias, the disease may follow a benign or asymptomatic course for many years
 many patients have no complaints at diagnosis
 for these chronic leukemias, treatment is not advocated in early asymptomatic stages, and there are no data supporting improvement in survival with
early intervention
-unlike acute leukemias and CML, CLL is
not considered curable, but it may follow an
indolent clinical course for many years.
Many patients have no complaints at diagnosis
and have only peripheral lymphadenopathy
or splenomegaly as a presenting
feature.
CLL is a slow-growing disease and many signs of CLL are vague. The symptoms of CLL tend to develop over time. For many people, CLL symptoms may at first seem to be some kind of non-specific change in overall health. There may be an increased sense of fatigue or weakness. Some people may experience flu-like symptoms, like night sweats or enlarged lymph nodes. Many people are diagnosed with CLL because of a blood test for an unrelated condition.
Some of the conditions that may arise as CLL slowly develops and spreads may include:
Anemia: Red blood transports oxygen throughout the body. Low levels of red blood cells may reduce the blood’s overall oxygen carrying capacity. This condition can be evaluated by a complete blood count (CBC) test. Symptoms of anemia may include weakness, fatigue, lack of energy and shortness of breath.
Leukopenia: Lymphocytic leukemias affect the white blood cells responsible for producing antibodies and warding off disease. A decrease in the functional lymphocytes may diminish the body's immune system. Symptoms of leukopenia may include reduced immunity, more frequent infections and fevers.
Thrombocytopenia: Blood platelets are the particles in the blood that aid with clotting. A CBC test may reveal a low blood platelet count in patients who have CLL. Symptoms of thrombocytopenia may include easy bruising, bleeding or nose bleeds, and bleeding gums.
Swollen lymph nodes: In some cases, the leukemia may spread to the lymph nodes. The clusters of lymph nodes in the neck, armpits or groin may become noticeably swollen from the accumulation of excessive amounts of cancerous lymphocytes.
Enlarged liver or spleen: The excess lymphocytes may build up in the liver or spleen. An enlarged liver or spleen may cause a feeling of fullness after eating a small meal, loss of appetite or swelling in the abdomen.
Treatment for CLL may include radiation therapy, chemotherapy, stem cell transplant and/or immunotherapy

18. Summary 3 main types of blood cancer: 4 main types of leukemia:
Leukemia – arises in progenitor lymphoid or myeloid cells
Lymphoma – arises in mature lymphocytes in secondary lymphoid tissue
Myeloma – arises in bone marrow plasma cells
4 main types of leukemia:
Acute lymphoblastic leukemia (ALL)
Chronic lymphocytic leukemia (CLL)
Acute myeloid leukemia (AML)
Chronic myeloid leukemia (CML)
2 main types of lymphoma:
Hodgkin’s lymphoma – presence of Reed-Sternberg cells
Non-Hodgkin’s lymphoma – absence of Reed-Sternberg cells
Multiple Myeloma: production of abnormal antibodies (M proteins
3 main types of blood cancer:
Leukemia: arises in progenitor lymphoid or myeloid cells
Lymphoma: arises in mature lymphocytes in secondary lymphoid tissue
Myeloma: arises in bone marrow plasma cells
4 main types of leukemia:
Acute lymphoblastic leukemia (ALL) – affects
Chronic lymphocytic leukemia (CLL)
Acute myeloid leukemia (AML)
Chronic myeloid leukemia (CML)
2 main types of lymphoma:
Hodgkin’s Lymphoma – presence of Reed-Sternberg cells
Non-Hodgkin’s Lymphoma – absence of Reed-Sternberg cells
Multiple Myeloma: production of abnormal antibodies (M proteins

19. References
Al-Farsi, Khalil. “Multiple myeloma: an update.” Oman medical journal vol. 28,1 (2013): doi: /omj
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Cancer Genome Atlas Research Network et al. “Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.” The New England journal of medicine vol. 368,22 (2013): doi: /NEJMoa
Chapel, Helen et al. Essentials Of Clinical Immunology. 6th ed. Chichester: Wiley Blackwell, Print.
Daver, Naval et al. “Targeting FLT3 mutations in AML: review of current knowledge and evidence.” Leukemia vol. 33,2 (2019): doi: /s
Davis, Amanda, Anthony Viera, and Monica Mead. "Leukemia: An Overview For Primary Care." American Family Physician. N.p., Available at:
Genetics Referencne. "Chronic Myeloid Leukemia." Genetics Home Reference. N.p., Available at:
Guerard, Emily J., and Michael R. Bishop. "Overview Of Non-Hodgkin's Lymphoma." Disease-a-Month 58.4 (2012): doi:
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Zhang, Jinghui et al. “Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.” Blood vol. 118,11 (2011): doi: /blood

20. Thank you for listening!