Dysregulation of BCL-2 family proteins by leukemia fusion genes

Abstract

The genomic lesions that characterize acute lymphoblastic leukemia in childhood include recurrent translocations that result in the expression of fusion proteins that typically involve genes encoding tyrosine kinases, cytokine receptors, and transcription factors. These genetic rearrangements confer phenotypic hallmarks of malignant transformation, including unrestricted proliferation and a relative resistance to apoptosis. In this Minireview, we discuss the molecular mechanisms that link these fusions to the control of cell death. We examine how these fusion genes dysregulate the BCL-2 family of proteins, preventing activation of the apoptotic effectors, BAX and BAK, and promoting cell survival. Recurrent fusion genes in acute lymphoblastic leukemiaAcute lymphoblastic leukemia (ALL) 2 is the most common form of childhood malignancy. Therapy for ALL is one of the great success stories of modern chemotherapy, and overall cure rates are now Ͼ90% in developed countries, depending on molecular subtypes and clinical features (1). The extraordinary improvements in outcomes in ALL have unquestionably been driven by the treatment of patients on international collaborative clinical trials (2), which have made it possible to rapidly recruit sufficient numbers of patients to studies of new treatment regimes. The analysis of treatment responses, based on measurement of minimal residual disease, has allowed the early identification of treatment failure or relapse and the consequent adjustment of treatment intensity.The next revolution in our understanding of ALL biology is being driven by many studies, involving thousands of patient samples, characterizing the genomic landscape of ALL through genome and transcriptome sequencing (3-7). This has led to the recognition of novel molecular subtypes of ALL, defined by the genomic lesions that drive them. Characterization of leukemic genomes provides insight into the key molecular pathways involved in ALL subtypes.Many recently identified genomic lesions in ALL are fusion genes, arising from chromosomal translocations (8). These include fusions that activate tyrosine kinases, cytokine receptors, and transcription factors. The presence of these fusions has important prognostic and treatment implications. In this Minireview, we consider how these genomic lesions promote resistance to apoptosis in ALL. Gene fusions in ALLChromosomal translocations, resulting in the expression of fusion genes, are a hallmark of B-cell malignancies. This likely arises as fusion partners are mistakenly juxtaposed during periods of genomic editing and recombinase-activating gene (RAG1 and RAG2) activation or somatic hypermutation during B-cell development (9). Recurrent chromosomal translocations have been recognized and detected in ALL, initially by staining of metaphases and microscopy, and more recently by fluorescent in situ hybridization (FISH). The detection of a small number of recurrent translocations is a standard component of ALL diagnosis and risk assessment. For example, t(12;21) ETV6-RUNX1 ...

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