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. What is AML?
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”

4. Where AML Originates
AML directly affects the formation of white blood cells including the neutrophils and monocytes. It occurs in the bone marrow and it forms malignancies known as myelomas

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