In vivo intraclonal and interclonal kinetic heterogeneity in B-cell chronic lymphocytic leukemia.
Clonal evolution and outgrowth of cellular variants with additional chromosomal abnormalities are major causes of disease progression in chronic lymphocytic leukemia (CLL). Because new DNA lesions occur during S phase, proliferating cells are at the core of this problem. In this study, we used in vivo deuterium ((2)H) labeling of CLL cells to better understand the phenotype of proliferating cells in 13 leukemic clones. In each case, there was heterogeneity in cellular proliferation, with a higher fraction of newly produced CD38+ cells compared with CD38- counterparts. On average, there were 2-fold higher percentages of newly born cells in the CD38+ fraction than in CD38- cells; when analyzed on an individual patient basis, CD38+ (2)H-labeled cells ranged from 6.6% to 73%. Based on distinct kinetic patterns, interclonal heterogeneity was also observed. Specifically, 4 patients exhibited a delayed appearance of newly produced CD38+ cells in the blood, higher leukemic cell CXC chemokine receptor 4 (CXCR4) levels, and increased risk for lymphoid organ infiltration and poor outcome. Our data refine the proliferative compartment in CLL based on CD38 expression and suggest a relationship between in vivo kinetics, expression of a protein involved in CLL cell retention and trafficking to solid tissues, and clinical outcome.
The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, USA.
Carlo
C
Calissano
Rajendra N
RN
Damle
Gregory
G
Hayes
Elizabeth J
EJ
Murphy
Marc K
MK
Hellerstein
Carol
C
Moreno
Cristina
C
Sison
Matthew S
MS
Kaufman
Jonathan E
JE
Kolitz
Steven L
SL
Allen
Kanti R
KR
Rai
Nicholas
N
Chiorazzi
D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D018941:Antigens, CD19 / Q000032:analysis; D001402:B-Lymphocytes / Q000166:cytology*; D018956:CD5 Antigens / Q000032:analysis; D002455:Cell Division; D002634:Chemotaxis, Leukocyte; D002869:Chromosome Aberrations; D002999:Clone Cells / Q000166:cytology*; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000378:metabolism; D003903:Deuterium / Q000032:analysis; D018450:Disease Progression; D006801:Humans; D016130:Immunophenotyping; D019394:Ki-67 Antigen / Q000032:analysis; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D017254:Leukemic Infiltration / Q000473:pathology; D008562:Membrane Glycoproteins / Q000032:analysis; D014411:Neoplastic Stem Cells / Q000166:cytology*; D019718:Receptors, CXCR4 / Q000032:analysis; D016615:Telomere / Q000648:ultrastructure; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000032:analysis
D018941:Antigens, CD19; D018956:CD5 Antigens; C527276:CXCR4 protein, human; D004273:DNA, Neoplasm; D019394:Ki-67 Antigen; D008562:Membrane Glycoproteins; D019718:Receptors, CXCR4; D003903:Deuterium; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1