Maike Buchner Srividya Swaminathan Zhengshan Chen Markus M€ uschen Mechanisms of pre-B-cell receptor checkpoint control and its oncogenic subversion in acute lymphoblastic leukemia Authors’ address Maike Buchner 1 , Srividya Swaminathan 1 , Zhengshan Chen 1 , Markus M€ uschen 1 1 Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA. Correspondence to: Markus M€ uschen Department of Laboratory Medicine University of California San Francisco 513 Parnassus Ave San Francisco, CA 94143, USA Tel.: +1 415 502 0388 Fax: +1 415 476 3726 e-mail: markus.muschen@ucsf.edu Acknowledgement This work is supported by grants from the NIH/NCI through R01CA137060, R01CA139032, R01CA157644, R01CA169458 and R01CA172558 (to M.M.), Translational Research Program grants from the Leukemia and Lymphoma Society (grants 6132-09, 6097-10 and 6221-12). M.M. is a Scholar of the Leukemia and Lymphoma Society and a Senior investigator of the Wellcome Trust. The authors have no conflicts of interest. This article is part of a series of reviews covering Hematologic Malignancies appearing in Volume 263 of Immunological Reviews. Summary: Pre-B cells within the bone marrow represent the normal counterpart for most acute lymphoblastic leukemia (ALL). During normal early B-cell development, survival and proliferation signals are dominated by cytokines, particularly interleukin-7 (IL-7) for murine developing B cells. With expression of a functional pre-B-cell receptor (BCR), cyto- kine signaling is attenuated and the tonic/autonomous pre-BCR signaling pathway provides proliferation as well as differentiation signals. In this review, we first describe checkpoint mechanisms during normal B-cell development and then discuss how genetic lesions in these pathways function as oncogenic mimicries and allow transformed pre-B cells to bypass checkpoint control. We focus on cytokine receptor signaling that is mimicked by activating lesions in receptor subunits or downstream mediators as well as aberrant activation of non-B lymphoid cytokine receptors. Furthermore, we describe the molecular switch from cytokine receptor to pre-BCR signaling, how this pathway is of particular impor- tance for certain ALL subtypes, and how pre-BCR signaling is engaged by genetic lesions, such as BCR-ABL1. We discuss the transcriptional control mechanisms downstream of both cytokine- and pre-BCR signaling and how normal checkpoint control mechanisms are circumvented in pre-B ALL. Finally, we highlight new therapeutic concepts for targeted inhibi- tion of oncogenic cytokine or pre-BCR signaling pathways. Keywords: cytokine receptor signaling, pre-B-cell receptor checkpoint, acute lympho- blastic leukemia, oncogenic mimicry Malignant transformation occurs via mimic of physiologically relevant pathways B-cell development is an orchestrated process involving cell- extrinsic and cell-autonomous signaling components such as cytokines, receptors, signaling intermediates, and transcrip- tion factors. A coordinated interplay of these factors enables robust B-cell production and limits proliferation to avoid autoimmunity and the emergence of B-lymphoid malignan- cies. In this review, we describe normal survival pathways and checkpoint mechanisms during early B-cell development and then discuss how oncogenic mimicry of these mecha- nisms emulates central survival and proliferation signals and allows precursor B-cell clones to bypass checkpoint control. Immunological Reviews 2015 Vol. 263: 192–209 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 0105-2896 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 192 Immunological Reviews 263/2015