Acute Myelogenous Leukemia and its Impact on the Immune System

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					Acute Myelogenous Leukemia
and its Impact on the Immune
           System


  By: Chelsea Counselman
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”
             What is AML?
 The term                 Results from acquired
  Myelogenous denotes       genetic damage to the
  what type of cell is      DNA of the bone
  being affected:           marrow
  Monocytes and            Immature cells
  Neutrophils               produced are known
 Acute refers to rapid     as “blast cells”
  progression forming
  immature cells
Where AML Originates
AML affects the multipotential
    hematopoietic cells
   Platelets
   Basophils: 1 of 3 types
    of granuloytes
   Neutrophils
   Monocytes
   Eosinophils: another
    type of granulocyte
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
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
    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
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?
        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
        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)
          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
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
         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
      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
          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
               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
       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

				
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posted:3/29/2008
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