Applications of DNA Microarray Technology in Cancer Research - DNA Microarray Technology and Data Analysis in Cancer Research - page 15

pMSCV-P210BCR/ABL-IRES-GFP

LTR P210 BCR/ABL IRES GFP

LTR

pMSCV-IRES-GFP

LTR IRES GFP

LTR

(a) (b)

Fig. 2.1. BCR-ABL induces both myeloid (CML) and lymphoid (B-ALL) diseases in
mice . (a) The retroviral constructs used to transduce the P210BCR-ABL and GFP genes.
( b) Wright/Giemsa staining of peripheral blood smears from mice with CML.

Although BCR-ABL induces both CML and B-ALL, here we only
focus on the induction of CML by BCR-ABL. By retrovirally expressing
the BCR-ABL oncogene in bone marrow cells, which are derived from
donor BALB/c mice pretreated with 5-fluorouracil (5-FU), we are now
able to produce CML in 100% of syngeneic recipients within 4 weeks
(Li et al ., 1999). The same CML can also be induced in C57BL/6 (B6)
and other inbred strains. Mouse CML is characterized by leukocytosis
with greatly elevated numbers of maturing neutrophils [Fig. 2.1(a)],
organ infiltration, and splenomegaly. The target cells for BCR-ABL are
primitive multipotential hematopoietic stem cells (Li et al ., 1999), pre-
cisely mimicking most of the pathological characteristics of human
CML. Myeloid cells transduced by the BCR-ABL oncogene express
BCR-ABL protein (Li et al ., 1999). The control retroviral vector con-
taining only the GFP gene [Fig. 2.1(b)] has never induced CML in recip-
ient mice within 12 months (data not shown). We carried out a microarray
study to identify genes that are regulated by BCR-ABL in cell lines and
in our mouse CML model.

2.3.1. Leukemia mouse model study

2.3.1.1. Rationale

The Abl tyrosine kinase inhibitor imatinib has become the most effective
drug for leukemia therapy, and has been shown to induce a complete hema-
tologic response in all interferon-resistant chronic-phase CML patients