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Lee S.-Y.,Fox Chase Cancer Center | Coffey F.,Fox Chase Cancer Center | Fahl S.P.,Fox Chase Cancer Center | Peri S.,Fox Chase Cancer Center Philadelphia | And 9 more authors.
Immunity | Year: 2014

Gradations in extracellular regulated kinase (ERK) signaling have been implicated in essentially every developmental checkpoint or differentiation process encountered by lymphocytes. Yet, despite intensive effort, the molecular basis by which differences in ERK activation specify alternative cell fates remains poorly understood. We report here that differential ERK signaling controls lymphoid-fate specification through an alternative mode of action. While ERK phosphorylates most substrates, such as RSK, by targeting them through its D-domain, this well-studied mode of ERK action was dispensable for development of γδ Tcells. Instead, development of γδ Tcells was dependent upon an alternative mode of action mediated by the DEF-binding pocket (DBP) of ERK. This domain enabled ERK to bind a distinct and select set of proteins required for specification of the γδ fate. These data provide the first invivo demonstration for the role of DBP-mediated interactions in orchestrating alternate ERK-dependent developmental outcomes. © 2014 Elsevier Inc.

Barta S.K.,Fox Chase Cancer Center Philadelphia | Joshi J.,Yeshiva University | Mounier N.,Center Hospitalier University lArchet Nice France | Xue X.,Yeshiva University | And 11 more authors.
British Journal of Haematology | Year: 2016

Central nervous system (CNS) involvement is reportedly more common in acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARL). We describe factors and outcomes associated with CNS involvement at baseline (CNSB) and relapse (CNSR) in 886 patients with newly diagnosed ARL. Of 886 patients, 800 received either intrathecal (IT) therapy for CNSB or IT prophylaxis. CNSB was found in 13%. CNSB was not associated with reduced overall survival (OS). There was no difference in the prevalence of CNSB between the pre-combination antiretroviral therapy (cART) and cART eras. 5·3% of patients experienced CNSR at a median of 4·2 months after diagnosis (12% if CNSB; 4% if not). Median OS after CNSR was 1·6 months. On multivariate analysis, only CNSB [hazard ratio (HR) 3·68, P = 0·005] and complete response to initial therapy (HR 0·14, P < 0·0001) were significantly associated with CNSR. When restricted to patients without CNSB, IT CNS prophylaxis with 3 vs. 1 agent did not significantly impact the risk of CNSR. Despite IT CNS prophylaxis, 5% of patients experienced CNSR. Our data confirms that CNSR in ARL occurs early and has a poor outcome. Complete response to initial therapy was associated with a reduced frequency of CNSR. Although CNSB conferred an increased risk for CNSR, it did not impact OS. © 2016 John Wiley & Sons Ltd.

Hayakawa K.,Fox Chase Cancer Center Philadelphia | Formica A.M.,Fox Chase Cancer Center Philadelphia | Colombo M.J.,Fox Chase Cancer Center Philadelphia | Ichikawa D.,Juntendo University | And 3 more authors.
Annals of the New York Academy of Sciences | Year: 2015

B cells generated early during fetal/neonatal B-1 development in mice include autoreactive cells with detectable CD5 upregulation induced by B cell receptor (BCR) signaling (B1a cells). A fraction of B1a cells are maintained by self-renewal for life, with the potential risk of dysregulated growth and progression to chronic lymphocytic leukemia (CLL)/lymphoma during aging. In studies using the Eμ-hTCL1 transgenic mouse system, it became clear that this B1a subset has a higher potential than other B cell subsets for progression to CLL. We have generated several autoreactive germline BCR gene models to compare B cells generated under conditions of natural exposure to autoantigen. Analysis of the mice has been key in understanding the importance of the BCR and BCR signaling for generating different B cell subsets and for investigating the cellular origin of B-CLL. © 2015 New York Academy of Sciences.

Li Y.-S.,Fox Chase Cancer Center Philadelphia | Zhou Y.,Fox Chase Cancer Center Philadelphia | Tang L.,Fox Chase Cancer Center Philadelphia | Shinton S.A.,Fox Chase Cancer Center Philadelphia | And 2 more authors.
Annals of the New York Academy of Sciences | Year: 2015

Fluorescence-activated cell sorting (FACS)-purified pro-B cells from fetal liver and adult bone marrow generate B cells with distinct phenotypes: fetal cells generate few IgDhigh B cells and half express CD5, whereas adult cells generate mostly IgDhigh cells and few express CD5. These results led us to propose a model of a developmental switch in B lymphopoiesis, similar to the well-known switch in fetal to adult erythropoiesis. More recent global analysis of mRNA and microRNA expression comparing these two types of pro-B cells revealed differential expression of Lin28b and microRNAs from the Let-7 family, indicating that this regulatory axis plays a role in the switch. Further analysis has provided data supporting this model, implicating Arid3a as a key transcription factor in mediating fetal-type B cell development. Function of this regulatory axis in human B lineage precursors may also explain the predominance of CD5+ B cells in cord blood. We suggest that Lin28b-promoted B cell development generates many cells expressing CD5 as a consequence of positively selected self-reactivity. While such cells serve a useful role in clearance of senescent cells and in certain immune responses, they also carry the risk of progression to leukemia/lymphoma later in life. © 2015 New York Academy of Sciences.

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