title: 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 newIGHV-D-Jmutations 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 inIGHV-unmutated andIGHV-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.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.; King's College London, Department of Haematological Medicine, London, United Kingdom.
authors.forename: Piers E M
authors.initials: PE
authors.lastname: Patten
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferrer
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
authors.forename: Shih-Shih
authors.initials: SS
authors.lastname: Chen
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Simone
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Marsilio
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yan
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Gitto
authors.affiliation: Department of Applied Mathematics and Statistics, State University of New York, Stony Brook, New York, USA.
authors.forename: Chaohui
authors.initials: C
authors.lastname: Yuan
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.; Department of Medicine, Hofstra Northwell School of Medicine, Manhasset, New York, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.; Department of Medicine, Hofstra Northwell School of Medicine, Manhasset, New York, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Barrientos
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.; Department of Medicine, Hofstra Northwell School of Medicine, Manhasset, New York, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.; Department of Medicine, Hofstra Northwell School of Medicine, Manhasset, New York, USA.
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.affiliation: Department of Applied Mathematics and Statistics, State University of New York, Stony Brook, New York, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: MacCarthy
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.; Department of Medicine, Hofstra Northwell School of Medicine, Manhasset, New York, USA.; Department of Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chu
authors.affiliation: The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.; Department of Medicine, Hofstra Northwell School of Medicine, Manhasset, New York, USA.; Department of Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi