BCR-ABL in Chronic Myelogenous Leukemia – How Does It Work?

Abstract

The discovery of the BCR-ABL fusion gene on the Philadelphia (Ph) chromosome in 1985 was the start of a new era in understanding the molecular basis of hematologic malignancies. It provided the rationale for producing first imatinib and then a series of small molecules designed to inhibit the tyrosine kinase activity of the Bcr-Abl oncoprotein, all of which can induce complete cytogenetic remissions in the majority of patients with chronic myelogenous leukemia (CML) in the chronic phase. However, we still do not know for sure whether the BCR-ABL fusion gene is really the initiating lesion for the chronic phase of CML and we have an incomplete understanding of the so-called genomic instability that underlies the production of the fusion gene and predisposes the Ph-positive clone to acquire further genetic events that lead to advanced-phase disease. Moreover, it is clear that though some of the mutant Ph-positive subclones that develop in patients taking tyrosine kinase inhibitors (TKIs) are the direct cause of the resistance observed, in other cases, its cause is unclear. It is likely that in the next few years we will see (1) improved methods for predicting responses to TKIs, (2) the use of TKIs in combination with other effective molecules such as farnesyl transferase inhibitors, and (3) a gradual reduction in the proportion of chronic-phase patients resistant to therapy.

Targeting of Leukemia-Initiating Cells to Develop Curative Drug Therapies: Straightforward but Nontrivial Concept

“…They may develop in most, many, or only a few subclones, and may either be detectable at diagnosis (prominent subclone/s) or they remain undetectable for a longer time period as they develop in slowly cycling LSC in small subclones [16,[77][78][79]. Nevertheless, as soon as the smaller subclones acquire a sufficient number of additional hits (mutations), they can expand and develop into an overt disease (relapse) in which neoplastic cells and LSC exhibit acquired resistance [77][78][79][80]. The use of targeted drugs must lead to a selection of these more malignant subclones over time.…”

“…Tyrosine kinase mutations particularly contribute to resistance against oncoprotein-targeting drugs such as BCR/ABL TKI or drugs directed against other critical kinases regulating growth or survival in LSC. The best studied model is CML, where multiple mutations in the BCR/ABL kinase domain have been identified in imatinibtreated patients [77][78][79][80]. However, resistance-related mutations have been detected in virtually all oncogenic kinases that play an important role in human leukemogenesis or myeloproliferation [81][82][83].…”

Sudden blastic crisis and additional chromosomal abnormalities during chronic myeloid leukemia in the imatinib era

“…24 Although the mechanism is not clear, in our patient, the transformation may have been associated with the acquisition of an additional Ph+ chromosome, independent of the initial Ph+ clone, because it is possible that a Ph-positive stem cell bearing a more aggressive mutation could be held in G0 for some time, and that this would still have the potency to generate BP after many years of apparently successful treatment. 25 Our patient could not be tested for BCR-ABL mutations.…”

Cancer‐associated neochromosomes: a novel mechanism of oncogenesis

“…Creation of novel chimeric loci producing a fusion transcript becomes a possibility. Many translocations in several tumour types result in this type of lesion: for example t(9:22) and BCR-ABL in chronic myelogenous leukaemia (45) or the t (15)(16)(17) and PML-RARA in acute promyelocytic leukaemia. (46) Another type of disruption occurs when an amplicon boundary truncates the coding sequence of a gene flanking the boundary, as recently shown in atypical chronic myeloid leukaemia.…”