Fig. 7: Predicted effects of loss of function of FOXO1 compared with FOXO3/PRDM1 on pre-B cell development.

A In the first phase of normal pre-B cell development, the newly assembled pre-BCR transduces signals through PI3K which together with IL7R signalling strongly activates the JAK/STAT and RAS pathways, which drive a limited period of clonal expansion of large pre-BII cells. The FOXO transcription factors are inactivated by phosphorylation and nuclear exclusion through PI3K driven activation of AKT. B The maturing pre-BCR signalosome activates BLNK which suppresses AKT activity leading to FOXO de-phosphorylation and nuclear translocation. FOXO1 activates the IRF4/CXCR4 feed forward loop resulting in escape from IL7R signalling through cell migration away from the IL7 high/CXCR12 low towards the CXCR12 high/IL7R low stromal niche. Activity of both FOXOs is reinforced by a second feed forward loop involving PRDM1 and these three genes together with CXCR4 contribute to the pre-B to immature B cell maturation program. PRDM1 likely reinforces cell cycle exit permitted by escape from IL7R signalling through displacement of transcription factors such as IRF2 and PAX5 and recruitment of transcriptional repressors such as histone deacetylases HDAC1 and 2 and the histone methyle transferases EHMT2 (G9A) and PRMT5. FOXO3 and PRDM1 also contribute to the maintenance of energy deficit, caused by rapid clonal expansion at the large pre-B cell stage, by inducing genes involved in the suppression of glycolysis. C With loss of FOXO1 function (ΔFOXO1), our data predict that IRF4/CXCR4 signalling would be severely compromised, preventing escape from IL7R signalling and initiation of the pre-B to immature B cell maturation program. However, energy deficit, maintained by FOXO3, would prevent unlimited clonal expansion and transformation to leukaemia. D With loss of FOXO3 and PRDM1 function (ΔFOXO3/ΔPRDM1) through deletion of chromosome 6, although the IRF4/CXCR4 axis would remain largely intact, there would be some effect on the normal pre-B cell transcriptional program. Crucially, suppression of glycolysis and maintenance of energy deficit would be compromised, contributing to an environment permissive for continued cell growth and leukemic transformation.