From genes to therapy: the case of Philadelphia chromosome-positive leukemias.
The Philadelphia chromosome (Ph-chromosome) has long represented the only cytogenetic abnormality known to be associated with a specific malignant disease in humans, being present in more than 95% of patients with chronic myelogenous leukemia. This abnormality is the result of a reciprocal translocation between the long arms of chromosome 9 and 22, t(9;22)(q34;q11), and its presence is not restricted to chronic myelogenous leukemia, but can also be found in 30% of cases of acute lymphoblastic leukemia in adults. In the 1980s, the molecular counterpart of the chromosomal rearrangement was identified to consist of the juxtaposition of parts of the BCR and ABL genes to form a BCR-ABL hybrid gene. The resulting chimeric proteins (P210 and P190), which retain constitutively activated tyrosine kinase activity, have demonstrated a causative role in the genesis of the leukemic process. Although many aspects of the BCR-ABL driven transformation remain unsolved, great advances in understanding the molecular pathology of Ph-positive leukemias resulted in meaningful improvement in the clinical setting. Molecular tools to diagnose disease (PCR, FISH, and southern blot) and to monitor minimal residual disease after potential curative treatment are now in current practice, and new powerful therapeutic tools have emerged that target the molecular oncogenic pathways activated in Ph-positive cells. Among them, specific ABL tyrosine kinase inhibitors recently obtained extraordinary results in many clinical protocols. This review summarizes the most recent advances in this field with special focus on the putative mechanisms of the transformation and progression of chronic myelogenous leukemia and on the major impact that understanding the molecular biology of these diseases is having in clinical practice.
Cilloni
Daniela
D
Department of Clinical and Biological Sciences, University of Turin, Hospital S. Luigi Gonzaga, 10043, Orbassano-Torino, Italy.
Guerrasio
Aagelo
A
Giugliano
Emilia
E
Scaravaglio
Patrizia
P
Volpe
Gisella
G
Rege-Cambrin
Giovanna
G
Saglio
Giuseppe
G
D002471:Cell Transformation, Neoplastic / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000628:therapy; D010677:Philadelphia Chromosome; D014178:Translocation, Genetic