Acute Leukemias - Republican Scientific Medical Library

a 14.2 · Molecular Biology of the Ph Chromosome 179
14.2.1 Lineage Restriction
of the Ph Chromosome
The fact that the same p210 BCR-ABL translocation can
be found in both CML and ALL, begs the question
whether or not CML lymphoid blast crisis (CML-LBC)
and Ph+ ALL are the same, or different, diseases. Since
CML is thought to arise in a multipotent “stem cell,” the
Ph might be expected to be found both in lymphoid
blasts and myeloid cells in CML-LBC, whereas ALL
arises in a lymphoid restricted progenitor, the Ph might
be expected to be found in lymphoid blasts, but not
myeloid cells in true Ph+ ALL. Unfortunately, studies
of lineage involvement in Ph+ ALL patients have not
yielded such a straightforward answer. There are cases
described of both p190 and p210 Ph+ ALL lymphoid
lineage restricted disease [13–21], in addition to cases
showing multilineage [13–17, 20–22]. In addition, cases
with convincingly documented CML-LBC have been
shown, predictably, to have multilineage involvement
[15, 19]. There is a suggestion that Ph+ ALL with involvement
of the myeloid lineage has a better outcome
than lymphoid-restricted disease [14, 15, 17]. Thus, under
the Ph+ ALL term a somewhat heterogeneous group
of diseases seem to be included: (1) a lymphoid lineage
restricted ALL that can be either p190 or p210, the majority
of p190 cases would be included in this group; (2)
a “stem cell” ALL with the Ph (either p190 or p210) present
in both lymphoid and myeloid lineages, bearing
BCR-ABL; and (3) occasionally misclassified CML-
LBC, a “stem cell” leukemia with the p210 BCR-ABL
variant.
More recent reports argue that the leukemic stem
cell (LSC) in p190 ALL originates in the hematopoietic
stem cell compartment. This p190 bearing cell has the
ability to renew itself, although it appears to be a lymphoid-restricted
precursor that does not express B-lineage
markers [23, 24]. Moreover, Castor et al. [21] found
that in the mouse model system, CD34+CD38-CD19cells
from p210 Ph+ ALL leukemia would not reconstitute
NOD-SCID mice with leukemia, while CD19+ precursors
could. Thus, while the Ph may arise in progenitors
in different stages of differentiation yielding different
lineage involvement, the leukemic stem cell with the
ability to self perpetuate seems to be lymphoid committed
in Ph+ ALL.
14.2.2 The Molecular and Cell Biology
of the Ph Chromosome
The abnormal activation of ABL, a result of the chimeric
BCR-ABL, has a central role in the transformation of
Ph+ leukemic cells. Aberrant expression of the BCR-
ABL tyrosine kinase increases proliferation, inhibits
apoptosis, and alters cell-adhesion properties. Several
animal models have been used in transplantation or
transgenic approaches to demonstrate that BCR-ABL
activity is sufficient to cause leukemogenesis. Such effects
can be demonstrated using either the p210 or
p190 BCR-ABL construct. However, the introduction
of the p190 or p210 BCR-ABL gene appears to yield
somewhat different types of leukemia. Transgenic 190
BCR-ABL mice develop a virulent leukemia that is restricted
to the pre-B lymphocytes. These mice typically
die of disease early, with 50% mortality by 10 weeks [25,
26]. In contrast, p210 BCR-ABL mice develop B, T, and
myeloid leukemias, and have a more chronic disease,
with the 50% mortality occurring at approximately
30 weeks [27]. A bone marrow transduction model
has been used to place a p210 BCR-ABL retroviral construct
in mice [28]. These animals typically developed
clonal myeloproliferative disease followed by the onset
of acute lymphoma/leukemia similar to blast crisis.
The data suggest that p190 BCR-ABL drives a more
virulent, lymphoid-biased disease process, whereas
p210 BCR-ABL tends to target a disease more resembling
CML.
The wild-type ABL protein, a nonreceptor tyrosine
kinase, has low enzymatic activity and is predominantly
localized to the cytoplasm, with a lower level of presence
in the nucleus. BCR-ABL, both p210 and p190,
are cytoplasmic in leukemic cell lines reflecting the normal
BCR location [29]. It is unclear which of the genetic
pathways inappropriately activated by BCR-ABL are
necessary for malignant transformation, and whether
additional genetic “hits” are required (or if the oncogenic
process is different between CML and Ph+
ALL). Thus, pathways involved in cell proliferation,
namely the RAS-MAPK, JAK-STAT, and PI3K pathways,
are aberrantly activated by BCR-ABL. The anomalous
activation of the RAS signaling cascade is achieved
when BCR-ABL complexes directly with the adaptor
protein Grb2, which, when coupled to the RAS guanine
nucleotide releasing protein SOS, interacts with and activates
RAS [30]. Stat5 appears to phosphorylated in
BCR-ABL cells, though neither Stat5a nor Stat5b appear