Regulation of the level of apoptosis in haemopoiesis could potentially provide a mechanism for regulating stem and progenitor cell population size. Thus, if there is substantial overproduction of stem or progenitor cells and compensatory loss by apoptosis during normal haemopoiesis, it would be possible to increase mature cell production in response to demand (e.g. anaemia, neutropenia), by reducing the level of apoptotic cell loss. It would be also be possible for dysregulation of apoptosis to lead to leukaemia.

The chromosomal translocation t(9;22) is the hallmark of chronic myeloid leukemia (CML), and results in the fusion of 5’ end of BCR gene 22q11 with 3’ end of ABL gene on 9q11 known as Philadelphia (Ph+) chromosome. This translocation is seen in 20% of adult ALL, 5% of pediatric ALL’s and rarely in AML. Anti-apoptotic effects, high proliferation and defects in the adhesion mechanism between primitive progenitor cells and stromal cells are considered to result from BCRABL fusion protein. These defects are therefore likely to be responsible for myeloid expansion, and these include defects in adhesion [1], self-renewal [2], insensitivity to negative regulators [3] and defects in apoptosis (see below). In CML, proliferation is increased and resistance to apoptosis has been proposed as a mechanism accounting for myeloid cell expansion. When BCR-ABL is transduced into haemopoietic cell lines, they become growth factor independent. A reduction of apoptosis might result in the expansion of progenitor cells in CML.

Several studies have shown that cell lines transfected with BCRABL are protected from apoptosis [4-6]. BCR-ABL protects growth factor-dependent murine cell lines from apoptosis caused by growth factor deprivation, irradiation and exposure to chemotherapeutic agents. This suggests that p210 may increase the survival of CML cells and rescue them from undergoing apoptosis. Several investigators have shown that CML progenitors are as sensitive as normal marrow to growth factor deprivation or irradiation [7-12].

Additionally, an increase in Fas/CD95 expression has been found on myeloid progenitor cells from patients with CML [13]. Preisler’s group [14] shows a significant difference in the Bcl-2 expression among accelerated phase-CML and BC-CML patients compared both to treated and untreated chronic phase-CML patients. Interestingly, the expression of Bcl-2 is downregulated after treatment with a signal transduction inhibitor (Imatinib, STI571 Novartis), showing involvement of this protein in the pathogenesis of CML [15]. Deletions or mutations of p53 have been noted in many hematological disorders (e.g CML) [16]. Similarly, recent data confirmed the involvement of apoptosis in CML [17-20].

In conclusion, we be l i e v e tha t apoptotic signaling will continue to occupy a central position in CML biology, and may facilitate designing a better therapeutic model for this disease.