Acute Myeloid Leukemia Pathophysiology

By Dr Ananya Mandal, MD

Cancer arises when the genes and DNA within the cell are damaged. In a normal cell this DNA guides the actions, functions, growth, maturity, division and ultimately death of the cell.

Cancer is usually caused if there is an alteration or mutation of DNA. The changes in the DNA can cause normal bone marrow cells to become leukemia cells.

Oncogenes and tumor suppressor genes

There is presence of normal genes that help cells to grow. These are called Oncogenes. Yet other types of genes that slow growth of cells are called tumor suppressor genes. These tumor suppressor genes slow down cell growth and division or cause them to die at appropriate times. Cancer occurs when this balance between Oncogenes and tumor suppressor genes is altered.

Types of DNA error

Common errors seen in DNA are called mutations. Translocations are the most common type of DNA change that form the basis of leukemia. A translocation means that DNA from one chromosome breaks off and becomes attached to another chromosome. This break off at a chromosome can turn on oncogenes or turn off tumor suppressor genes leading to cancers.

Myeloblasts

The malignant cells in AML are the myeloblasts. The myeloblast is an immature precursor of myeloid white blood cells. This myeloblast matures into a mature white blood cell.

In AML a single myeloblast may undergo the genetic change that fixes the cell in its immature state and prevents maturation and differentiation.

In the majority of cases this mutation alone is incapable of causing leukemia. When this mutation and arrest in the immature stage is combined with other mutations which disrupt genes controlling proliferation (Oncogenes) the condition may give rise to AML.

Leukemic transformation can occur at a number of different steps along the differentiation pathway of the myeloblasts. The classification of AML follows the stage at which the maturation of the myeloblasts is arrested.

Cytogenetic abnormalities

Patients with AML in addition may have specific cytogenetic abnormalities. These abnormalities may predict the prognostic significance of the type of AML as well.

The abnormalities or mutations code for an abnormal gene that in turn makes abnormal fusion proteins. These abnormal proteins are usually transcription factors that may finally lead to arrest of differentiation.

For example, in acute promyelocytic leukemia (APL) a translocation t(15;17) produces a PML-RARα fusion protein. This binds to the retinoic acid receptor element in the promoters of several myeloid-specific genes and inhibits myeloid differentiation.

Reviewed by April Cashin-Garbutt, BA Hons (Cantab)

Sources

  1. http://www.nhs.uk/Conditions/Leukaemia-acute/Pages/Causes.aspx
  2. http://www.cancer.org/acs/groups/cid/documents/webcontent/003110-pdf.pdf
  3. http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/leukemia/pdf/amlguide.pdf
  4. http://www.ascp.org/PDF/Books/Chapter-18.pdf
  5. http://www.leukaemia.com/fileadmin/dl-docs/booklets/2008_booklet_acute_myeloid_leukaemia.pdf

Further Reading

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