Mechanisms of pre-B-cell receptor checkpoint control and its oncogenic subversion in acute lymphoblastic leukemia.

Maike Buchner, Srividya Swaminathan, Zhengshan Chen, Markus Müschen

Immunological reviews 2015 Jan

filter terms:

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 rece ptor (BCR), cytokine 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 importance 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 inhibition of oncogenic cytokine or pre-BCR signaling pathways. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Citation

Maike Buchner, Srividya Swaminathan, Zhengshan Chen, Markus Müschen. Mechanisms of pre-B-cell receptor checkpoint control and its oncogenic subversion in acute lymphoblastic leukemia. Immunological reviews. 2015 Jan;263(1):192-209