Acute Myelogenous Leukemia Acute Myelogenous Leukemia and its Impact on the Immune and its Impact on the Immune

SystemSystem

By: Chelsea Counselman

Acute Myelogenous LeukemiaAcute Myelogenous Leukemia

It is more commonly known as AMLIt is a cancer of the blood that affects the

cells producing myeloid blood cells First recognized in 1830 in GermanyPhysician referred to it as “weisses blut”The term leukemia stems from the Greek

words “leukos” and “haima”

What is AML?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”

Where AML OriginatesWhere AML Originates

AML affects the multipotential AML affects the multipotential hematopoietic cellshematopoietic cells

Platelets Basophils: 1 of 3 types

of granuloytes Neutrophils Monocytes Eosinophils: another

type of granulocyte

Types of Hematopoietic Cells Types of Hematopoietic Cells AML AffectsAML 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

What AML looks like under the What AML looks like under the microscopemicroscope

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).

AML and its Impact on the AML and its Impact on the Immune SystemImmune System

AML affects the innate immune systemSecondary Immune System kicks inThe proliferation of immature neutrophils

and moncytes takes placeUnable to leave the bone marrow to go into

blood stream and tissues to fight off infections

Questions That Scientists are Questions That Scientists are Trying to AnswerTrying 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?

Genetic AssociationsGenetic 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

Genetic Associations Genetic Associations ContinuedContinued

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)

Class 1 mutationsClass 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

Tyrosine KinasesTyrosine 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

Class 2 mutationsClass 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

Causes and SymptomsCauses 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

Current ResearchCurrent 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

SummarySummary

Acute Myelogenous Leukemia is caused by an mutations of myeloid progenitor cells

Causes immature cells to form called blastsThey cannot mature which causes a

reduction of normal WBCs in circulationAML is caused by genetic abberations such

as chromosomal translocations

Summary ContinuedSummary 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