Cell biology of CML cells

Abstract

At the cellular level, expansion of haemopoiesis in chronic myeloid leukaemia (CML) must involve some imbalance in cell production along the myeloid maturation pathway. The relevant kinetic parameters are cell loss by apoptosis and differentiation and cell gain by proliferation (self-renewal). In spite of the predominance of the BCR-ABL-positive leukaemic cells, some BCR-ABL-negative, presumably normal, progenitor cells remain for long periods in chronic phase CML. Thus, understanding the kinetics of CML and normal progenitor cells may lead to therapeutic strategies capable of reducing malignant cell growth and reactivating normal haemopoiesis.

Identification of genes potentially involved in disease transformation of CML

“…Delayed apoptosis is a feature of early phase CML, 16 but even more so of advanced disease stages in which upregulation of Table 2b Primer sequences Q-PCR BCR-ABL is a common event. 17.…”

Chronic myelogenous leukemia: mechanisms underlying disease progression

“…Although the p210 BCR/ABL itself does not significantly affect terminal cell differentiation in chronic phase, differentiation is blocked in blast phase CML. [93][94][95] The role of BCR-ABL itself or other events in this phenomenon is not fully elucidated. Additional mutations, formation of new oncogenes, elevated cytokine levels, inactivation of tumor suppressor genes are hypothetical reasons for this phenomenon.…”

Combination of interferon alpha with either Ara-C or ATRA in vitro reduces the selective action of interferon against CML CFU-GM

“…This results in the juxtaposition and fusion of parts of the BCR and ABL genes on the Philadelphia (Ph) chromosome and the production of a protein tyrosine kinase (p210 bcr/abl ) that is presumed to be responsible for the biological and clinical features of the disease. 1,2 Interferon (IFN)-␣ has been used to treat CML patients with beneficial results in terms of haematological response and re-emergence of Ph chromosome-negative haemopoiesis. 3,4 Moreover, there is a significant survival advantage compared with alternative forms of chemotherapy.…”

“…More recently, we have found that the tyrosine kinase inhibitor, STI571, also preferentially suppresses the replating ability of CML CFU-GM. 12 Since the CFU-GM compartment is the fastest expanding component of the myeloid series in untreated CML, 2,13,14 these findings suggest that at least part of the mode of action of IFN-␣ and STI571 is to selectively reduce the expansion of the leukaemic clone at the myeloid progenitor cell level.…”