Biomedical Engineering Reference
In-Depth Information
phosphorylation of the substrate. Once this signaling pathway is blocked, the
leukemic transit-amplifying cells are free to differentiate, and they eventually
die by apoptosis.
Acute Promyelocytic Leukemia
Differentiation of APL cells is induced by treatment with retinoic acids, which
react with the fusion gene product and cause its degradation (Melnick and
Licht, 1999; Soignet et al., 1997). The fusion gene is the promyelocytic
leukemia (PML) protein gene fused with the retinoic acid receptor gene.
The fusion product (PML
RARa) inactivates the PML protein, which is
required for normal formation of granules and for maturation of the pro-
myelocyte. Reaction of retinoic acid with the fusion protein results in
ubiquitinization and degradation of the protein. The maturation arrest is
thereby removed, and the leukemic cells are free to differentiate (Melnick
and Licht, 1999).
Acute Myeloid Leukemia
The situation for AML is much more complex than for CML or APL. The
complexity arises because there is more than one molecular lesion in AML. The
lesions fall into two functional classes: Class I, proliferative, and Class II,
apoptosis inhibitory (Chalandon and Schwaller, 2005). Class II lesions by
themselves cause myelodysplasia. The transition to AML occurs when both a
Class I lesion and a Class II lesion are present, usually because a second
mutation occurs in a cell already bearing a lesion. The combination of a
proliferative lesion with loss of apoptosis is a double whammy, resulting in
AML (Chalandon and Schwaller, 2005). Because there are at least two lesions in
AML, specific differentiation therapy requires that both lesions be treated.
Thus, so far, such therapy has met with limited success, since agents for only
one of the two signals are available in most cases.
Leukemic Stem Cells and Differentiation Therapy
As in the case for chemotherapy and radiation therapy, when differentiation
therapy is discontinued, the leukemia will re-form from resistant leukemic
stem cells. Chemotherapy and radiotherapy act on the transit-amplifying cells
of the tumor, but the tumor stem cells are resistant. Differentiation therapy
removes the block tomaturation and allows the cancer transit-amplifying cells
to differentiate and die. Again, however, the tumor stem cells are not suscep-
tible, so that when differentiation therapy is discontinued, the tumor will
regrowformfromthecancerstemcell(Sell,2004a,2006a;Reyaetal.,
2001). At the end of this chapter, specific approaches to inhibition of the
cancer stem cells using differentiation therapy will be discussed (see also
Sell, 2006a).
