Biomedical Engineering Reference
In-Depth Information
cells. From that observation, we would predict that AML should be transplan-
table via any of the blast cells of the leukemia, but, in fact, the tumor transit-
amplifying cells of human leukemia seem not to be able to initiate leukemia
upon transplantation into SCID mice (Sutherland et al., 1996; Bonnet and
Dick, 1997). Thus, tumor initiation is a property only of the leukemic stem
cell. On the other hand, as recently discussed by Kelly et al. (2007), the trans-
plantability of human leukemias in SCID mice may be limited by difficulties
experienced by human cells in adapting to a foreign (mouse) milieu. In fact,
Kelly et al. found, similar to Furth and Kahn (1937), that mouse AML can be
transplanted to non-irradiated histocompatible recipients via any leukemic cell.
Although there are still inconsistencies in the identification of leukemic stem
cells, it is clear that leukemias arise from a block in the differentiation of cells in
the myeloid pathway (maturation arrest; Sell, 2005).
Maturation Arrest Is the Critical Lesion in Leukemia
Myeloid leukemia is clinically classified on the basis of how rapidly the disease
progresses, without treatment, into acute, subacute, or chronic, although there
are many intermediate variations. Chronic myeloid leukemia (CML) is due to a
maturation arrest at the myelocyte level; acute promyelocytic leukemia (APL) is
due to an arrest at the promyelocyte level;, and acute myeloid leukemia (AML)
is due to an arrest at the myeloid progenitor cell level. The stages of maturation
arrest are directly related to gene rearrangements that result in constitutive
activation of the cells (Sell, 2005).
An illustrative example is the gene translocations responsible for Burkitt's
lymphoma, a B-cell tumor. The translocations leading to Burkett's lymphoma
result in the insertion of an immunoglobulin promoter next to the c-myc gene
(activates proliferation) and/or the Bcl2 gene (blocks apoptosis). Although the
gene translocations occur in every cell of the body (including the hematopoietic
stem cells and lymphocytic stem cell) in transgenic mice with these fusion genes,
the molecular lesion is only manifested in cells that activate the Ig promoter, i.e.,
B cells (Cory et al., 1999; Park et al., 2005). Thus, the stage of maturation arrest
is determined by the point of differentiation at which the promoter of the fusion
transgene is activated.
Many translocations have now been identified in myeloid leukemia (Rowley,
1975). For the purposes of this discussion, only three situations will be pre-
sented here: (1) the t9:22 bcr-abl translocation (Philadelphia chromosome) in
CML, which results in constitutive activation of tyrosine phosphorylase
(Nowell, 1974); (2) the t15:17 PML/RARa translocation in APL; and (3) two
of many possible translocations in AML: t12:13 (FLT3; IL-3R), which activates
kinases, and 13q12 ITD FLT3, which blocks apoptosis. The stage of matura-
tion arrest for each of these leukemias is determined by the level at which the
transgene product acts (Fig. 2D). Specific differentiation therapy can be direc-
ted toward these lesions (Sell, 2005).
