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 ...

Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in vitro. The combination demonstrated greater efficacy than standard chemotherapeutics and TKIs in primary samples from adult B-ALL with Ph+ ALL, Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL samples. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph− and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.