title: Divergence in CD19-mediated signaling unfolds intraclonal diversity in chronic lymphocytic leukemia, which correlates with disease progression.
abstract: Emerging data on intraclonal diversity imply that this phenomenon may play a role in the clinical outcome of patients with chronic lymphocytic leukemia (CLL), where subsets of the CLL clone responding more robustly to external stimuli may gain a growth and survival advantage. In this study, we report intraclonal diversity resolved by responses to CD19 engagement in CLL cells, which can be classified into CD19-responsive (CD19-R) and -nonresponive subpopulations. Engagement of CD19 by anti-CD19 Ab rapidly induced cellular aggregation in the CD19-R CLL cells. The CD19-R CLL cells expressed higher surface levels of CD19 and c-myc mRNA, exhibited distinct morphological features, and were preferentially abolished in rituximab-treated patients. Both subpopulations reacted to sIgM stimulation in a similar manner and exhibited similar levels of Akt and Erk phosphorylation, pointing to functional signaling divergence within the BCR. CD19 unresponsiveness was partially reversible, where nonresponding CD19 cells spontaneously recover their signaling capacity following incubation in vitro, pointing to possible in vivo CD19-signaling attenuating mechanisms. This concept was supported by the lower CD19-R occurrence in bone marrow-derived samples compared with cells derived from the peripheral blood of the same patients. CLL patients with >15.25% of the CD19-R cell fraction had a shorter median time to treatment compared with patients with <15.25% of CD19-R cell fraction. In conclusion, divergence in CD19-mediated signaling unfolds both interpatient and intraclonal diversity in CLL. This signaling diversity is associated with physiological implications, including the location of the cells, their responses to anti-CLL therapeutics, and disease progression.
authors.affiliation: Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Herishanu
authors.forename: Sigi
authors.initials: S
authors.lastname: Kay
authors.forename: Nili
authors.initials: N
authors.lastname: Dezorella
authors.forename: Shoshana
authors.initials: S
authors.lastname: Baron
authors.forename: Inbal
authors.initials: I
authors.lastname: Hazan-Halevy
authors.forename: Ziv
authors.initials: Z
authors.lastname: Porat
authors.forename: Svetlana
authors.initials: S
authors.lastname: Trestman
authors.forename: Chava
authors.initials: C
authors.lastname: Perry
authors.forename: Rony
authors.initials: R
authors.lastname: Braunstein
authors.forename: Varda
authors.initials: V
authors.lastname: Deutsch
authors.forename: Aaron
authors.initials: A
authors.lastname: Polliack
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Naparstek
authors.forename: Ben-Zion
authors.initials: BZ
authors.lastname: Katz
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D018941:Antigens, CD19 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D000069283:Rituximab; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D000069283:Rituximab; D002784:Cholesterol