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Origins of acute myeloid leukemia or AML

A recent study, published in Nature on Feb. 12, 2014, has identified the cells from which acute myeloid leukemia (AML) evolves from. These pre-leukemic cells have distinct genetic and functional properties and can persist after remission following chemotherapy.

AML is the most common acute leukemia affecting adults.
AML is the most common acute leukemia affecting adults.
Anita P. Kuan, Source: American Cancer Society
A sample from an AML patient. AML is the most common acute leukemia affecting adults, and its incidence increases with age. The incidence of AML is expected to increase as the population ages.
Armed Forces Institute of Pathology (AFIP)

In Connecticut, approximately 280 deaths from leukemia (all kinds) occur every year. Every year, approximately 24,090 Americans die from leukemia (all kinds), about 10,460 of these deaths are from AML.

AML is a cancer of the bone marrow and the blood. It affects mostly cells that aren't fully developed. These cells can't carry out their normal functions. The word "acute" in acute myeloid leukemia signifies the disease's rapid progression. The word “myeloid” indicates that AML affects a group of white blood cells called the myeloid cells (myeloid cells normally develop into the various types of mature blood cells, such as red blood cells, white blood cells, and platelets). The word “leukemia” means an abnormal increase of white blood cells in the blood; namely, a cancer of white blood cells).

Aggressive leukemias are often diagnosed “out of the blue”, without any previous signs of cancer. It is thought that these sudden cases of cancer arise from “silent” precursor cells that are transient and have no clinical impact. This recent study provides evidence that the early-stage cells of AML are, in fact, persistent and have distinct genetic and functional properties.

Cancer arises when cells accumulate mutations over time. In AML, the first cell to be transformed to a cancer-like state is typically a hematopoietic stem cell (HSC). Differentiation of this cell can lead to AML. This recent study specifically identifies these cells and establishes the sequential order of mutations in them that leads to AML. The researchers also note that these cells are the ancestors of the dominant cloned cells found in AML (a large proportion of patients with AML have pre-leukemic HSCs). These pre-leukemic HSCs can out-compete normal HSCs in their ability to convert into the different cell types that sustain normal hematopoiesis (blood-cell development).

Researchers found that, when AML presents in the clinic with no warning, the cancer-initiating mutation in the HSC is often in the gene DNMT3a. These precancerous cells are not clinically detectable. Further mutations (for example in the gene NPM1) then lead to AML.

These findings provide insights into the processes that lead to the development of leukemia. The possible clinical implications of these results include the potential to target the known mutations to destroy pre-leukemic cells before they acquire further mutations that make them resistant to therapy.

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