IGHV-unmutated and IGHV-mutated chronic lymphocytic leukemia cells produce activation-induced deaminase protein with a full range of biologic functions.
Clonal evolution occurs during the course of chronic lymphocytic leukemia (CLL) and activation-induced deaminase (AID) could influence this process. However, this possibility has been questioned in CLL because the number of circulating AID mRNA(+) cells is exceedingly low; synthesis of AID protein by blood CLL cells has not been demonstrated; the full range of AID functions is lacking in unmutated CLL (U-CLL), and no prospective analysis linking AID expression and disease severity has been reported. The results of the present study show that circulating CLL cells and those within secondary lymphoid tissues can make AID mRNA and protein. This production is related to cell division because more AID mRNA was detected in recently divided cells and AID protein was limited to the dividing fraction and was up-regulated on induction of cell division. AID protein was functional because AID(+) dividing cells exhibited more double-stranded DNA breaks, IGH class switching, and new IGHV-D-J mutations. Each of these actions was documented in U-CLL and mutated CLL (M-CLL). Furthermore, AID protein was associated with worse patient outcome and adverse cytogenetics. We conclude that the production of fully functional AID protein by U-CLL and M-CLL cells could be involved in clonal evolution of the disease.
The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030, USA.
Piers E M
PE
Patten
Charles C
CC
Chu
Emilia
E
Albesiano
Rajendra N
RN
Damle
Xiao-Jie
XJ
Yan
Dorothy
D
Kim
Lu
L
Zhang
Amanda R
AR
Magli
Jacqueline
J
Barrientos
Jonathan E
JE
Kolitz
Steven L
SL
Allen
Kanti R
KR
Rai
Sergio
S
Roa
Patricia K
PK
Mongini
Thomas
T
MacCarthy
Matthew D
MD
Scharff
Nicholas
N
Chiorazzi
D001483:Base Sequence; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D014407:Tumor Cells, Cultured; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D012333:RNA, Messenger; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase