Acute Myelogenous Leukemia and its Impact on the Immune System

1. Acute Myelogenous Leukemia and its Impact on the Immune System By: Chelsea Counselman

2. Acute Myelogenous Leukemia • It is more commonly known as AML • It is a cancer of the blood that affects the cells producing myeloid blood cells • First recognized in 1830 in Germany • Physician referred to it as “weisses blut” • The term leukemia stems from the Greek words “leukos” and “haima”

3. The term Myelogenous denotes what type of cell is being affected: Monocytes and Neutrophils Acute refers to rapid progression forming immature cells Results from acquired genetic damage to the DNA of the bone marrow Immature cells produced are known as “blast cells” What is AML?

4. Where AML Originates

5. AML affects the multipotential hematopoietic cells • Platelets • Basophils: 1 of 3 types of granuloytes • Neutrophils • Monocytes • Eosinophils: another type of granulocyte

6. Types of Hematopoietic Cells AML Affects • Neutrophils and monocytes • Production is blocked and immature blast cells form • Cannot mature and differentiate correctly • Build up of immature cells in bone marrow prevents the production of other essential cell types • Causes decreased rate of self-destruction and cellular differentiation

7. What AML looks like under the microscope • This microscope image shows AML cells (acute myeloblastic leukemia; also referred to as ANLL, acute nonlymphocytic leukemia). Certain internal cell structures are typical of AML. These include prominent nucleoli (red arrows) and cytoplasmic granules (grainy structures inside the cell which indicate some degree of cell maturation--black arrow).

8. AML and its Impact on the Immune System • AML affects the innate immune system • Secondary Immune System kicks in • The proliferation of immature neutrophils and moncytes takes place • Unable to leave the bone marrow to go into blood stream and tissues to fight off infections

9. Questions That Scientists are Trying to Answer • What is the target cell where the original mutation occurred and which tumor cells have the capacity to sustain or re-initiate the tumor?

10. Genetic Associations • Research states that AML is caused by genetic aberrations such as translocations between chromosomes that alter the function of transcriptory regulatory factors • These translocations are a direct result of chimeric fusion proteins which are caused by the abnormal cells and its inability to allow further growth, proliferation, maturation and differentiation. • Class 1 and 2: mutations responsible for the development of the neoplastic process of myeloproliferation and de-differentiation

11. Genetic Associations Continued • Class 1: mutations that give rise to proliferation and/or differentiation and are made from tyrosine kinases (TK); they have no affect on differentiation • Class 2: mutations that interfere with terminal differentiation and apoptosis thereby providing survival advantage for the mutated cells; associated with Core Binding Factors (CBFs)

13. Class 1 mutations • Involved with TKs which regulate cell proliferation, migration, differentiation, and survival. • TKs are located on growth factor receptors which contain an extracellular domain for binding ligands, transmembrane domain, and an intracellular tyrosine kinase domain • Growth factor binds to extracellular domain causing phosphorylation

14. Tyrosine Kinases • Tyrosine kinases are also known as oncogenes • Oncogenes are present in the mutated neutrophils and moncytes • AML activates them causing uncontrollable proliferation, apoptosis, decreased adhesion, and inhibits differentiation

15. Class 2 mutations • Have CBFs which have two transcriptory subunits :CBFα and CBFβ • This is where chromosome translocation most commonly takes place • It also is the site where the gene AML1 regulates cell maintenance and expansion as well as survival of hematopoietic cells

16. Causes and Symptoms • It is not inherited; rather it’s a genetic abnormality that results from damage to the DNA of developing cells in the bone marrow • Actual causes are unknown • Risk factors that are attributed include: exposure to radiation, exposure to chemicals such a benzene, patients who have received chemotherapy and radiotherapy previously

17. Current Research • Examining the post-transitional modifications of nucleosomal proteins and methylation of particular DNA sequences on chromatin • Marks on chromatin are a result of enzymes that are embedded in multi-subunit machineries • Enzymes are primary target for new anti-cancer drugs • Studies using HDACs and DNA methyltransferase inhibitors suggest that reverse of the chromatin sequences can be done by these drugs

18. Summary • Acute Myelogenous Leukemia is caused by an mutations of myeloid progenitor cells • Causes immature cells to form called blasts • They cannot mature which causes a reduction of normal WBCs in circulation • AML is caused by genetic abberations such as chromosomal translocations

19. Summary Continued • Most commonly caused by Class 1 and 2 mutations • These mutations prevent proliferation, differentiation, apoptosis, and survival of normal myeloid cells • AML affects the innate and adaptive immune systems which affects the body from fighting off infections