Sunday, July 05, 2009

New targeted therapy finds and eliminates deadly leukemia stem cells

Insecure people who are derisive or dismissive of technical scientific terminology (which they affectedly disdain as "jargon") can miss a lot of significant meaning.

Consider the medical term "leukemia", which is familiar to the public as referring to a form of blood cancer. It's related to the less familiar term "leukocyte", which refers to various kinds of white blood cells. (The prefix "leuko-" is derived from Greek leukos, meaning "white". The suffix, "-cyte" is also Greek: kytos, meaning "cell".)

Leukocytes were originally recognized as distinct from other types of cells in the blood, especially "red" blood cells, which derive their color from iron-containing hemoglobin. There are actually a number of different types of leukocytes – and different types of corresponding leukemias. One common subtype of leukemia involves myeloid cells (myelocytes), which are normally found in bone marrow and occur as precursors to several types of blood cells. Acute myeloid leukemia (AML, also known as acute myelogenous leukemia) is the most common example, and has several subtypes itself.

Leukocytes of many types are derived from myeloid cells, which are thus a type of stem cell. When such cells develop certain types of abnormalities they harmfully overproduce derived cells, effectively making them cancer (specifically, leukemia) stem cells. The most common type of abnormality is a type of cell surface receptor known as CD123. A receptor is simply a protein found on a cell surface which binds to external cell signaling proteins called cytokines. (There's the "cyto-" again. The "-kine" part is from Greek kinos, which refers to motion, as in "kinetic".)

Cytokines are often interpreted by cells as signals to divide and proliferate, usually in a helpful way, as normal with immune system cells. Certain immune-system cytokines are called interleukins, because they facilitate signaling among immune system leukocytes. CD123 receptors, in particular, are receptors for interleukin-3. Thus CD123 receptors have another name: interleukin-3 receptor, alpha.

CD123 is essential for the normal communication between immune system cells such as T cells. It must exist on the surfaces of cells that need to respond to interleukin-3, in order to have a proper immune system response to infection. You do not, however, want CD123 on stem cells, whose excessive proliferation results in leukemia.

And so it is that one promising treatment for acute myeloid leukemia involves the development of a novel antibody, called 7G3, that can block CD123 receptors without triggering proliferation. Of course, that might interfere with immune system function – but such interference is preferable to leukemia.

New Targeted Therapy Finds And Eliminates Deadly Leukemia Stem Cells (7/2/09)
Associate Professor Lock [senior study author] and colleagues exploited the fact that the molecule CD123 is expressed at very high levels on LSCs but not on normal blood cells. CD123 is part of the interleukin-3 receptor, a protein that interacts with a growth factor (called a cytokine) that influences cell survival and proliferation. The researchers created a therapeutic antibody that recognized and bound to CD123 with the hope that this antibody would selectively interfere with AML-LSC survival.

When AML-LSCs from human patients were transplanted into mice treated with the antibody, called 7G3, cytokine signaling in the tumor cells was blocked. Further, 7G3 impaired migration of the AML-LSCs to bone marrow and activated the innate immune system of the host mouse to destroy the AML-LSCs. Overall, treatment with 7G3 substantially improved mouse survival when compared with control groups. The researchers go on to report that a CD123-targeting antibody is currently being used in phase 1 clinical trials of advanced AML and that there are no signs of treatment-related toxicity.

Update, 8/14/09: Here's another research effort that's targeting CD123 in AML: New discovery points to a new treatment avenue for acute myeloid leukemia (7/6/09)

Further reading:

New Drug Hits Leukemia Early (7/2/09) – Science News article

Monoclonal Antibody-Mediated Targeting of CD123, IL-3 Receptor α Chain, Eliminates Human Acute Myeloid Leukemic Stem CellsCell Stem Cell research article

Tags: , cancer stem cell

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