Chronic myelogenous leukemia: mechanisms underlying disease progression

Abstract

Chronic myelogenous leukemia (CML), characterized by the BCR-ABL gene rearrangement, has been extensively studied. Significant progress has been made in the area of BCR-ABLmediated intracellular signaling, which has led to a better understanding of BCR-ABL-mediated clinical features in chronic phase CML. Disease progression and blast crisis CML is associated with characteristic non-random cytogenetic and molecular events. These can be viewed as increased oncogenic activity or loss of tumor suppressor activity. However, what causes transformation and disease progression to blast crisis is only poorly understood. This is in part due to the lack of a good in vivo model of chronic phase CML even though animal models developed over the last few years have started to provide insights into blast crisis development. Thus, additional in vitro and in vivo studies will be needed to provide a complete understanding of the contribution of BCR-ABL and other genes to disease progression and to improve therapeutic approaches for blast crisis CML.

Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts

“…25 In vitro cotreatment with ATO enhances selective cytotoxic effects of STI571 against Bcr-Abl+ leukemia cells. 26 In CML, a disease whose leukemic cells demonstrate an aberrant activation of intracellular signals, 27 the association of an anti-MEK1 compound with STI571 is promising. 28 MEK1 inhibitors were tested in combinations with the checkpoint abrogator UCN-01 to obtain a strong apoptosis in drug-sensitive and -resistant myeloma cells.…”

Fusion tyrosine kinases: a result and cause of genomic instability

“…Genomic instability in FTK induced leukemias and lymphomas is manifested by the accumulation of chromosomal aberrations and mutations leading to malignant progression of the disease and acquired resistance to small molecule inhibitors such as IM (Ott et al, 1998;Wlodarska et al, 1998;Villamor et al, 1999;Salloukh and Laneuville, 2000;Shet et al, 2002;Brain et al, 2003;Nardi et al, 2004;Nowicki et al, 2004).…”

“…Genetic aberrations leading to malignant progression of the disease CML cells accumulate genetic abnormalities during the course of the disease (Rowley and Testa, 1982;Alimena et al, 1987;Johansson et al, 2002;Shet et al, 2002;Calabretta and Perrotti, 2004). The aberrations associated with the progression of BCR/ABL-positive CML chronic phase to the aggressive blast crisis (CML-BC) include additional chromosomes (Ph 1 , þ 8, þ 19), isochromosome 17q (associated with the loss of p53), reciprocal translocations (3;21 and 7;11 -associated with the expression of AML-1/Evi-1 and NUP98/ HOXA9 fusion proteins, respectively), other translocations and inversions associated with AML/myelodysplasia (inv(3), t(15;17)), loss-of-heterozygosity at 14q32, homozygous mutations/deletions of pRb and p16/ARF, and mutations in p53 and RAS (reviewed by Calabretta and Perrotti, 2004).…”

Identification of genes potentially involved in disease transformation of CML

“…[2][3][4][5][6] Changes in proliferation, differentiation, apoptosis sensitivity, DNA repair function, as well as loss of imprinting and genomic instability have also been observed upon disease transformation. 7 In a small minority of cases of advanced stage CML, N-and K-RAS mutations have been reported. 8 The question which of these changes occurred as a cause or as a result of the transformation itself has not been solved yet.…”