Defective regulation of leukemic hematopoiesis in chronic myeloid leukemia
Introduction
The biology of chronic myeloid leukemia (CML) has fascinated and frustrated experimental hematologists for several decades. The fascination is triggered by several important and unique features of CML (Table 1). One of these is the clear delineation of the disease course in most patients into two phases: an initial chronic phase which is typically prolonged (years) and a later blast crisis which is usually untreatable and rapidly fatal. Because of the gross overproduction of granulocytes and sometimes platelets that occurs during the initial chronic phase, most patients become symptomatic and are diagnosed at this point. Accordingly, their cells can be readily obtained in large numbers and studied. Also, the `leukemic' cells present in patients with chronic phase CML differentiate normally. Therefore, current methodologies for detecting and quantitating hematopoietic progenitors, which require their ultimate differentiation into recognizable elements, are readily applicable to CML progenitors 1, 2. Finally, because of the long median duration of the chronic phase (i.e. 3–6 years [3]), treatments that require time to become effective can be considered. Progression to blast crisis is associated with the acquisition of changes that impede or perturb the normal differentiation process and result in a rapid accumulation of undifferentiated blasts. These overwhelm continued normal blood cell output and are, themselves, typically refractory to conventional agents used to treat acute leukemia.
A second important feature of CML is its association with the presence in the affected cells of the Ph chromosome [4]. The formation of this chromosome is now known to result from a fusion of the BCR gene and the c-ABL gene and the creation of a functional oncogene [5]. This gene rearrangement provides an essential and stable marker for discriminating normal and leukemic cells in populations where both of these genotypes are present. This is particularly relevant to analyses of samples obtained from chronic phase patients in whom the `leukemic' cells are otherwise indistinguishable, in most respects, from their normal counterparts. In addition, the identification of the BCR-ABL gene as a unifying abnormality in CML has focused attention on the mechanisms by which its product, p210BCR-ABL, causes the pathology that is characteristic of the disease.
The third feature of CML that makes it an attractive paradigm to study is the presumed origin of the leukemic cells in a hematopoietic stem cell with lymphoid as well as myeloid differentiation potential. This is inferred from the molecularly unique feature of the BCR-ABL gene rearrangement in the cells from each CML patient [5], thus proving that the BCR-ABL+ cells present must indeed arise from a single cell in each case. The fact that this initial cell is then able to continue generating recognizable lymphoid and myeloid progeny indefinitely (if not further altered) argues in favour of its undifferentiated state at the time when the BCR-ABL gene rearrangement occurred.
In summary, CML appears to arise in different individuals as a result of the same rare genetic event occurring in a member of the developmentally most interesting population of the hematopoietic system. This leads to a clonal expansion of the affected cell without interference in its ability to differentiate into essentially normal progeny causing an initially, relatively benign disease to develop. Nevertheless, in spite of the interest and opportunities this situation provides, most CML patients die within 6 years of their diagnosis because they are ineligible for, or refractory to, the only two treatment modalities shown unequivocally to offer longer term benefits, i.e. allogeneic marrow transplantation and the administration of high doses of α-interferon [6]. Disappointingly, knowledge of the underlying genetic lesion has not, even after more than a dozen years, revolutionized our understanding of what goes wrong or how to effectively interfere with or exploit such information. In fact, some of the most promising therapeutic developments now being pursued using autotransplants are based more on the discovery in the early 1980s of a large but suppressed population of residual normal stem cells in most CML patients at diagnosis [6].
On the other hand, a growing knowledge of the biological behaviour of primitive normal hematopoietic cells, and improved methods for their purification, measurement and manipulation is allowing a more refined picture of the abnormalities that characterize primitive CML cells to be delineated. In this review, we will summarize the current status of the information that our group has obtained in this area and a resultant model of how we think the neoplastic hematopoiesis in patients with CML is deregulated.
Section snippets
CML considered as a problem in cell traffic control
Current thinking views hematopoiesis as a one directional linear branching system involving a huge expansion of cell numbers and a finely tuned output of mature end cells with many potential intervening points of regulation. These serve to alter either the number or proportion of cells available for subsequent amplification. The number of cells available at any given place in the system for further amplification is dictated by the activation (or maintenance) of biochemical events that control
The hematopoietic hierarchy
Four classes of hematopoietic cells are now typically distinguished. These include: (1) terminally differentiating cells that have acquired, to varying extents, the morphological features of the mature elements of the lineage they represent; (2) a number of more primitive and rare progenitor populations which are called colony-forming cells (CFC) because they can generate colonies of from 20 to more than 104 morphologically recognizable (mature) cells when stimulated in a semi-solid matrix to
Abnormalities in cellular behaviour
All Ph+/BCR-ABL+ progenitor populations, regardless of their differentiated state or lineage commitment, have been found to contain more proliferating cells than their counterparts in normal individuals, even prior to the administration of any therapy 1, 46. At the level of the CFC, this finding is consistent with the observation that the leukemic elements within the various subpopulations of CFC conventionally distinguished are, on average, similarly amplified in a given patient. In addition,
Summary
Chronic phase CML represents an example of quantitatively, rather than qualitatively, perturbed hematopoiesis. It is characterized by an inexorable, but kinetically, extremely slow rate of expansion of a Ph+/BCR-ABL+ stem cell population that frequently includes <105 LTC-IC by the time of diagnosis. Nevertheless, these cells are able to generate very large numbers of more differentiated cells (totalling >1012 cells). The latter include proportionately normal ratios of erythroid,
Acknowledgements
Much of the work discussed in this review was supported by grants from the National Cancer Institute of Canada (NCIC) with funds from the Terry Fox Run and the Canadian Cancer Society and a grant from Novartis (Basel, Switzerland). The authors also thank Mrs. K. Lambie for collating the updated progenitor data and Ms. Bernadine Fox for expert assistance in preparing the manuscript. C.J. Eaves is a Terry Fox Cancer Research Scientist of the NCIC.
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