Essential Features Of The Bcrabl Protein

Mutational analysis of Bcr-Abl identified several domains and amino acid residues that are crucial to the molecule's capacity to transform hematopoietic cells. Most importantly, deletion of the tyrosine kinase function abrogates transformation and leukemogenicity,79 although more recent data suggest that even the kinase-dead protein may modify certain cellular functions, such as adhesion and migration.80 A second critical structural motif is the N-terminus of BCR that contains the dimerization domain.81 This domain can be replaced by other sequences that allow dimerization; for example, ETV-6 in the Etv-6-Abl fusion protein that has sporadically been found in patients with ALL.82 Since the N-terminus of Abl is crucial to the autoregulation of the kinase, it is conceivable that the principal consequence of dimerization is the abrogation of autoinhibition.6061 Many other motifs within Bcr-Abl have important functions but are not essential to leuke-mogenesis. Rather than that, they modulate the aggressiveness of the disease or influence its phenotype in murine models of Bcr-Abl-positive leukemia. For example, tyrosine 177 of BCR is crucial to the induction of myeloid but not lymphoid leukemia,83 and deletion of the Abl SH3 domain attenuates the disease.84

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