[Hematopoietic stem cells and hematopoietic neoplasias]

Pluripotent hematopoietic stem cells have been defined as cells with extensive self-renewal capacity and lympho-hematopoietic differentiation potential. Clonal selection of a stem cell as a first step in the progression to neoplasia can be achieved by an alteration of this self-renewal potency. Our current understanding of the pathogenesis of the myeloproliferative disorders including acute myeloid leukemias, chronic myeloproliferative disorders (CMPD) and myelodysplastic syndromes (MDS), is based on the assumption that they represent a clonal disorder resulting from transformation of a hematopoietic stem cell. However, when performing methods for determining X-chromosome inactivation in female patients as a clonality marker, a significant minority of the patients with Philadelphia chromosome negative (Ph(-)) CMPD and MDS exhibit polyclonal proliferation. The implications of these results are not yet clarified and the lack of a proven target cell impairs the understanding of the underlying molecular defect. In this context, altered response to cytokine stimulation in vitro provides indirect information concerning molecular dysregulation. A subset of patients with MPD present with translocations that facilitate molecular investigation and clonality proof. They nearly always result in rearrangements of at least one transcription factor gene. Most of these fusion genes are constitutively active, sending out continuous proliferative and antiapoptotic signals or activate an overlapping set of signalling pathways. The classical example for a balanced translocation is the t(9;22) bcr-abl aberration in chronic myelogeneous leukemia. Many other karyotypic abnormalities have also been associated with CMPD and MDS and involve deletions of chromosomes 20q, 13q, 1q, 7q and 5q as well as trisomy of 8 and 9. Our increased understanding of the hematopoietic stem cell compartment and the molecular basis of regulation of its self-renewal and differentiation bears a direct impact on our understanding of leukemia evolution and progression.