Chronic lymphocytic leukemia cells diversify and differentiate in vivo via a nonclassical Th1-dependent, Bcl-6–deficient process
Piers E.M. Patten, … , Charles C. Chu, Nicholas Chiorazzi
Piers E.M. Patten, … , Charles C. Chu, Nicholas Chiorazzi
Published April 7, 2016
Citation Information: JCI Insight. 2016;1(4):e86288. https://doi.org/10.1172/jci.insight.86288.
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Research Article Hematology Immunology

Chronic lymphocytic leukemia cells diversify and differentiate in vivo via a nonclassical Th1-dependent, Bcl-6–deficient process

Abstract

Xenografting primary tumor cells allows modeling of the heterogeneous natures of malignant diseases and the influences of the tissue microenvironment. Here, we demonstrate that xenografting primary chronic lymphocytic leukemia (CLL) B lymphocytes with activated autologous T cells into alymphoid mice results in considerable CLL B cell division and sizable T cell expansion. Nevertheless, most/all CD5+CD19+ cells are eventually lost, due in part to differentiation into antibody-secreting plasmablasts/plasma cells. CLL B cell differentiation is associated with isotype class switching and development of new IGHV-D-J mutations and occurs via an activation-induced deaminase-dependent pathway that upregulates IRF4 and Blimp-1 without appreciable levels of the expected Bcl-6. These processes were induced in IGHV-unmutated and IGHV-mutated clones by Th1-polarized T-bet+ T cells, not classical T follicular helper (Tfh) cells. Thus, the block in B cell maturation, defects in T cell action, and absence of antigen-receptor diversification, which are often cardinal characteristics of CLL, are not inherent but imposed by external signals and the microenvironment. Although these activities are not dominant features in human CLL, each occurs in tissue proliferation centers where the mechanisms responsible for clonal evolution operate. Thus, in this setting, CLL B cell diversification and differentiation develop by a nonclassical germinal center–like reaction that might reflect the cell of origin of this leukemia.

Authors

Piers E.M. Patten, Gerardo Ferrer, Shih-Shih Chen, Rita Simone, Sonia Marsilio, Xiao-Jie Yan, Zachary Gitto, Chaohui Yuan, Jonathan E. Kolitz, Jacqueline Barrientos, Steven L. Allen, Kanti R. Rai, Thomas MacCarthy, Charles C. Chu, Nicholas Chiorazzi

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Figure 2

CLL-derived plasma cells and plasma Ig only become apparent after leukemic cells have undergone many divisions.

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CLL-derived plasma cells and plasma Ig only become apparent after leukem...
(A) Human (h) CD45+CD5+CD19+CD38++ cells are only identified in spleen-residing cells 21 days after chronic lymphocytic leukemia (CLL) cell transfer. Cells increase in number afterward. Mean and SEM shown; 1-way ANOVA; n = 60 mice. (B) Representative FC plots of CFSE-labeled hCD45+CD5+CD19+ cells in spleen following transfer of U-CLL1122 (upper) and M-CLL1164 (lower). Note development of CD38++ phenotype with progressive division. (C) hCD45+CD5+CD19+ cells with a CD38++ phenotype are only apparent after >60% of CLL cells have undergone ≥6 divisions. Curve shows exponential relationship (r2 = 0.76; n = 60). (D) Plasma Igs are not detectable until CD38++ cells appear. Mean μg/ml and SEM shown for IgM and IgG; n = 60 mice. Above results obtained from 5 mice euthanized at each time point in 2 independent experiments involving U-CLL1122 and M-CLL1164 (total mice = 60; Table 1 and Supplemental Table 2). U-CLL, CLL clone with IGHV sequence differing ≤2% from most similar germline gene; M-CLL, CLL clone with IGHV sequence differing >2% from most similar germline gene; FC, flow cytometry.