Leukemias and Lymphomas Come From Normal Blood Cells

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1 Leukemias and Lymphomas Come From Normal Blood Cells by Steve Anderson, Ph.D. Steve Anderson has a Ph.D. in Immunology with 25 years experience in biomedical research. His scientific expertise includes immunology, immunological diseases, virology, and HIV pathogenesis. Cancers of the cells of the blood and immune system are called leukemias or lymphomas depending on where and in what kind of cell they originate. Leukemias originate in stem cells in the bone marrow, while lymphomas originate in mature cells in peripheral tissues such as lymph nodes. Leukemias and lymphomas arise from normal cells at a certain stage of maturation or differentiation. [Box 1] The leukemia and lymphoma cells retain many of the characteristics of the normal cells from which they are derived. The cells lineage, the kind of normal cell it started as, can tell us what kind of prognosis to expect. In some cases the cells physical and molecular characteristics can form the basis of specialized treatments aimed at one or more of these characteristics. Box 1. Definitions Differentiation: maturation, development of specific functions or characteristics. Differentiation is a continuous process in the development of blood cells. During the process the cells become increasing committed to becoming one type of cell and lose the ability to become others. Proliferation: the process in which cells multiply and increase in numbers. Terminal Differentiation: The stage at which a cell becomes fully mature, exhibits all of its highly specific functions, and is no longer able to proliferate. fully mature cell with all its specialized functions. This process is called differentiation. There are two major lineages, or branches, of blood cells: lymphoid cells (lymphocytes), and myeloid cells. Lymphocytes can be either T lymphocytes (T cells) or B lymphocytes (B cells). T cells get their name because their differentiation takes place in the thymus gland, while B cell differentiation takes place in the bone marrow. Where Do Blood Cells Come From? All blood cells and cells that make up your immune system come from your bone marrow. They all come from a special kind of cell called a hematopoietic stem cell (HSC). Stem cells have the ability to produce all of the different kinds of blood cells and immune cells that we need. Each of the different kinds of cells has a specialized function. Some are involved in clotting, others carry oxygen, others fight off foreign invaders such as bacteria, viruses, and allergens. [Table 1] The different kinds, or lineages, of cells can be thought of like a family tree. Each type of cell goes through several stages of development or maturation until it becomes a Nucleus Cytoplasm X RBCs don t have { a nucleus. Why do we always draw cells as two circles, one inside the other? Cells have two major parts: the nucleus, where the DNA and genes live, and the cytoplasm, where all the cell s machinery is. The shape of the nucleus can be used to identify certain kinds of cells. The nucleus is the Command and Control Center, the DNA and genes have all the instructions the cell needs to survive and make things. The cytoplasm is where all the building and demolition occurs. It s also where signals are communicated from the environment outside the cell to the nucleus. The cell s outer surface, or membrane, also is studded with a variety of proteins that the cell uses to sense it s environment. 1

2 Where Do Blood Cells Come From? Blood and immune cells are produced in the bone marrow by hematopoietic stem cells (HSCs). The diagram of blood cell development looks like a family tree. HSCs are self-renewing; that is, they make more of themselves so you don t run out. There are two major lineages of blood cells: lymphoid and myeloid. The lymphoid lineage gives rise to T cells, which develop in the thymus, and B cells, which develop in the bone marrow. The myeloid lineage gives rise to all the other kinds of blood cells: granulocytes, monocytes, Red Blood Cells (RBCs, erythrocytes), and platelets. After T cells and B cells reach maturity they meet again in lymph nodes where they form germinal centers. B cells develop further into plasma cells that make antibodies. BONE MARROW Self-renewing Hematopoietic Stem Cell (HSC) Common Myeloid Precursor (CMP) Red Blood Cells (RBCs) Common Lymphocyte Precursor (CLP) Platelets T lymphocytes THYMUS B lymphocytes Monocytes Granulocytes Basophils Neutrophils Eosinophils Plasma Cell CD8+ T killer Cell CD4+ T helper cell LYMPH NODE GERMINAL CENTER T B Antibodies BLOOD CELLS The myeloid lineage includes many different kinds of cells: granulocytes (neutrophils, basophils, eosinophils), monocytes, erythrocytes (RBCs), and platelets. All myeloid cell differentiation occurs primarily in the bone marrow. Why Are Lymph Node Germinal Centers Important? Did you know that your tonsils are lymph nodes? That s why they swell up when you get sick. As your T cells and B cells multiply in your tonsils, the tissue fills up with cells and becomes swollen, inflamed, and painful. Swollen tonsils are a sign that your immune system is at work. As the cells move through their differentiation program their capacity to divide and proliferate diminishes. Once the cells reach their final level of maturity they are no longer capable of dividing and have a finite life-span in the body. This is known as termi- nal differentiation. Lymphocytes are unique in that both T cells and B cells can undergo another round of proliferation and differentiation in lymph node germinal centers. During this new round of activation some B cells become plasma cells. Plasma cells are 2 antibody-making factories. Plasma cells eventually migrate back to the bone marrow where they continue to produce antibodies until they expire.

3 Leukemias and Lymphomas Begin As Normal Cells Thymus Lymph Node Germinal Center Leukemia and Lymphoma cells come from normal cells at a certain stage of differentiation. The type of cell the cancer comes from determines your diagnosis. Knowing what cell type leukemia or lymphoma cells look like allows us to place them on the map of normal blood cell development. Most leukemias come from immature cells in the bone marrow or thymus, while lymphomas usually come from mature T cells or B cells that have been reactivated in lymph node germinal centers. Hematopoietic Stem Cell Bone Marrow Nucleus is expelled Lymphoid T-ALL B-ALL B-CLL HL, NHL MM Myeloid CML AML Abbreviations: ALL, Acute Lymphocytic Leukemia; T-ALL, ALL with characteristics of T lymphocytes; B-ALL, ALL with characteristics of B lymphocytes; CLL, Chronic Lymphocytic Leukemia; CML, Chronic Myelogenous Leukemia; AML, Acute Myelogenous Leukemia; HL, Hodgkin s Lymphoma; NHL, Non-Hodgkin s Lymphoma; MM, Multiple Myeloma. Leukemia and Lymphoma Cells Resemble The Normal Cell Types From Which They Are Derived Cancer arises when a cell undergoing the normal differentiation process stops maturing and begins to multiply out of control. Cancer often starts from a mutation in just a single cell. Leukemia and lymphoma cells keep many of the specific functions and characteristics of the cell from which they originated. This is a fact that most people don t realize. That s how doctors and scientists are able to identify them. This feature of cancer cells also is a major reason why cancers are able to get a toe-hold in your body. Since they resemble a certain type of normal cell, your immune system doesn t recognize them as dangerous or foreign. The kind of cell that your cancer comes from determines your diagnosis, that is, what kind of leukemia or lymphoma you have, and can have an important impact on the prognosis and treatment of your cancer. The diagram shows which branch or lineage of cells each type of leukemia and lymphoma comes from. Because leukemias and lymphomas arise from normal cell types we can assign them to a particular location in the diagram of normal blood cell formation. 3 Acute Lymphocytic Leukemia (ALL) is a cancer of maturing lymphocytes. ALL can be further classified as T-ALL or B-ALL depending on whether the ALL cells have the characteristics of T cells or B cells. The same is true for Chronic Lymphocytic Leukemia (CLL), which nearly always comes from a B cell. Chronic Myelogenous Leukemia (CML) and Acute Myelogenous Leukemia (AML) come from the myeloid lineage. CML tends to have more characteristics of granulocytes but during blast crisis it can resemble any and all of the myeloid lineage cell types. AML is classified as M0 through M7, depending on which normal cell characteristics the leukemia cells have. M0 through M2 AMLs are undifferentiated. They most likely arise in a very

4 early immature cell and have few or no characteristics that indicate a particular cell type. M3 or Acute Promyelocytic Leukemia (APL) is a cancer that comes from an immature granulocyte called a promyelocyte. M4 and M5 are derived from immature monocytes. M6 is derived from cells early in the erythrocyte pathway, and M7 is derived from immature megakaryocytes. Lymphomas Arise in Lymph Node Germinal Centers Lymphomas arise from mature T lymphocytes (T cells) and B lymphocytes (B cells) rather than from immature cells as leukemias do. As we have already discussed, T cells and B cells become reactivated in lymph node germinal centers where they undergo a new phase of proliferation and differentiation in response to antigens. During this process, they become susceptible to mutations and the generation of cancer cells. This is why, as we see in the diagram, lymphomas such as Hodgkin s Lymphoma (HL) or Non-Hodgkin s Lymphomas (NHL) typically arise in lymph nodes and other secondary areas where mature lymphocytes are found. Since activation of B cells results in the generation of plasma cells, plasma cell cancers like Multiple Myeloma (MM) also are thought to originate in lymph nodes. Cell & Lineage-Based Treatment The type of leukemia or lymphoma you have can often help doctors predict how aggressive your cancer is going to be, where it is likely to migrate to, and what general or specific treatments the cancer is likely to respond to. For example, why does Multiple Myeloma (MM), which is a cancer that comes from plasma cells, cause severe bone lesions? Plasma cells normally migrate to the bone marrow where they live out their lives making antibodies. Since MM is a tumor of plasma cells, the MM cells are doing what plasma cells normally do they migrate to the bone marrow. In the case of MM, since the cells are multiplying rapidly, they disrupt the normal structure and function of the bone. In the case of CML we know that CML cells have a specific genetic mutation called the Philadelphia Chromosome (Ph1). The mutation on Ph1, called a BCR-ABL1 translocation, results in the formation of an abnormal protein, BCR-ABL1. Because BCR-ABL1 is not found in normal myeloid cells it is a potential target for the treatment of CML. The drug Gleevec (imatinib) was specifically Table 1. Blood Cell Functions Leukocytes T cells B cells Monocytes Neutrophils Basophils Eosinophils Erythrocytes Platelets White Blood Cells (Leuko=white) Develop in the thymus. CD4 T helper T cells activate other cells and orchestrate the immune response; CD8 killer T cells attack and kill virus-infected cells. Mature in the bone marrow. When they are activated, B cells become plasma cells that make antibodies to neutralize foreign invaders. Cells that ingest dead cells, bacteria, and debris, and also interact with lymphocytes to trigger an immune response. Cells that kill bacteria and foreign invaders by ingesting them and secreting toxic anti-microbial compounds from their granules. Most of the white blood cells in our blood are neutrophils. Play a major role in allergic reactions by secreting histamine from their granules. Play a major role in attacking parasites. Red Blood Cells (RBCs). (Erythro=red). Carry oxygen to our cells and tissues. Small cell fragments derived from megakaryocytes whose major function is to heal injuries to our tissues by forming clots. designed to attack cells having the BCR-ABL1 protein and has become a very effective treatment for CML. CML is a good example of where a specific drug was created based on the known characteristics of the cancer cells. There are a number of other myeloid cancers with different translocations where a similar approach is being used. Acute Promyelocytic Leukemia (APL) is another example of treatment based on a stage of differentiation. APL, a form of AML, is a cancer of cells in the differentiation pathway of granulocytes. APL is typically treated with a drug called ATRA (all trans-retinoic acid), with excellent results. Exposure of APL cells to ATRA causes them to resume differentiating or maturing into granulocytes and turns off their uncontrolled growth. This is an exciting case in which the process of terminal differentiation can be restored with a drug. For my last example you need to know that B cells have a protein on their outer surface called CD20. This is a protein who s expression is acquired during B cell differentiation and then remains as a protein common to all B cells. Many B cell leukemias and lymphomas also have CD20. Therefore we can use antibodies to the CD20 protein (Rituximab is the name for anti-cd20 antibodies) as a means of destroying the out-of-control B cells. The caveat is that at least some normal or good B cells will also be destroyed. Treatments like this must be used very carefully and often in combination with other therapies such as standard chemotherapy. 4

5 Resources Scientific Research Articles: Foon KA, Schroff RW, and Gale RP Surface Markers on Leukemia and Lymphoma Cells: Recent Advances. Blood 60: Shaffer AL, Rosenwald A, and Staudt LM Lymphoid Malignancies: The Dark Side of B-Cell Differentiation. Nature Reviews Immunology 2: Teitell MA and Pandolfi PP Molecular Genetics of Acute Lymphoblastic Leukemia. Annu. Rev. Pathol. Mech. Dis. 4: Textbooks: Atlas of Hematopathology. F. Naeim, P.N. Rao, S.X. Song, and W.W. Grody, Eds. Academic Press, Hematology for the Medical Student. A.H. Schmaier and L. M. Pertuzzelli, Eds. Lippincott Williams & Wilkins, Immunobiology. C.A. Janeway, P. Travers, M. Walport, and M. Shlomchik, Eds. Garland Publishing, Websites: BMTinfonet National Cancer Institute (NCI) Boston Children s Hospital Cancer.net Cleveland Clinic Lymphomainfo.net Genentech, Bio-oncology types/cll?cid=ga1_ps_ &c= &moc=mbbi UA7006&gclid=CLuUltypqrgCFY3m7AodjHkAJA Cancer Research UK incidence/all-cancers-combined/ American Society of Clinical Oncology (ASCO) National Comprehensive Cancer Network (NCCN) NCI Surveillance, Epidemiology and End Results (SEER) Program Centers for Disease Control (CDC) Blood Cancers Leukemia & Lymphoma Society Wikipedia: