Chronic myelogenous leukemia: molecular and cellular aspects

Chronic myelogenous leukemia (CML) originates in a pluripotent hematopoetic stem cell of the bone marrow and is characterized by greatly increased num bers of granulocytes in the blood. Myeloid and other hematopoetic cell line ages are involved in the process of clonal proliferation and differentiatio n. After a period of 4-6 years the disease progresses to acute-stage leukem ia. On the cellular level, CML is associated with a specific chromosome abn ormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangem ent between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoin t cluster region) gene on chromosome 22. Most of ABL is linked with a trunc ated BCR. The BCR/ABL fusion gene codes for an 8-kb mRNA and a novel 210-kD a protein which has higher and aberrant tyrosine kinase activity than the n ormal c-ABL-coded counterpart. Phosphorylation of a number of substrates su ch as GAP, GRB-2, SHC, FES, CRKL, and paxillin is considered a decisive ste p in transformation. An etiological connection between BCR/ABL and leukemia is indicated by the observation that transgenic mice bearing a BCR/ABL DNA construct develop leukemia of B, T, and myeloid cell origin. CML cells pro liferate and expand in an almost unlimited manner. Adhesion defects in bone marrow stromal cells have been proposed to explain the increased number of leukemic cells in the peripheral blood. However, findings of our laborator y have shown that the BCR/ABL chimeric protein that is expressed in transfe cted cells may, under certain conditions, also increase the adhesion to fib ronectin via enhanced expression of integrin. Our previous immunocytologica l studies on the expression of beta 1 and beta 2 integrins have found no qu alitative differences between normal and CML hematopoietic cells in vitro. Even long-term-cultured CML bone marrow or blood cells continuously express those adhesion molecules that are characteristic of the cytological type. Recent experiments indicate that certain early CML progenitors may adhere t o the stromal layer in vitro similarly to their normal counterparts. They c annot be completely removed by long-term culture on allogeneic stromal cell s. At present, the only curative therapy is transplantation of allogeneic h ematopoietic stem cells. Based on the molecular and cellular state of knowl edge of CML, new therapies are being developed. BCR/ABL antisense oligonucl eotides, inhibitors of tyrosine kinase, peptide-specific adoptive immunothe rapy or peptide vaccination, and restoration of hematopoiesis by autologous stem cell transplantation following CML cell purging are examples of impor tant approaches to improving CML treatment.