title: Investigating the role of CD38 and functionally related molecular risk factors in the CLL NOD/SCID xenograft model.
abstract: We explored the role of CD38 and functionally associated molecular risk factors in a recently described chronic lymphocytic leukemia (CLL) nonobese diabetic/ severe combined immunodeficient xenograft model. Intravenous injection of peripheral blood mononuclear cells from 73 patients with CLL into 244 mice resulted in robust engraftment of leukemic cells into the murine spleens detected 4 wks after transplantation. Leukemic cell engraftment correlated significantly (P < 0.05) with markers reflecting disease activity, e.g., Binet stage and lymphocyte doubling time, and the expression of molecular risk factors including CD38, CD49d, ZAP-70, and IgVH mutational status. Increased engraftment levels of CD38+ as compared to CD38- CLL cells could be attributed, in part, to leukemic cell proliferation as evidenced by combined immunostaining of murine spleen sections for Ki-67 and CD20. In short-term (24 h) homing assays, CD38+ CLL cells migrated more efficiently to the bone marrow of the recipient animals than their CD38- counterparts. Finally, CD38 expression by the leukemic cells was found to be dynamic in that it was regulated not only by elements of the murine microenvironment but also by co-engrafting non-malignant human T cells. This model could be useful for evaluating the biological basis of CLL growth in the context of the hematopoietic microenvironment as well as preclinical testing of novel compounds.
authors.affiliation: Department of Hematology, University of Duisburg-Essen Medical School, Essen, Germany.
authors.forename: Semra
authors.initials: S
authors.lastname: Aydin
authors.forename: Florian
authors.initials: F
authors.lastname: Grabellus
authors.forename: Lewin
authors.initials: L
authors.lastname: Eisele
authors.forename: Michael
authors.initials: M
authors.lastname: Möllmann
authors.forename: Maher
authors.initials: M
authors.lastname: Hanoun
authors.forename: Peter
authors.initials: P
authors.lastname: Ebeling
authors.forename: Thomas
authors.initials: T
authors.lastname: Moritz
authors.forename: Alexander
authors.initials: A
authors.lastname: Carpinteiro
authors.forename: Holger
authors.initials: H
authors.lastname: Nückel
authors.forename: Ali
authors.initials: A
authors.lastname: Sak
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Göthert
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dührsen
authors.forename: Jan
authors.initials: J
authors.lastname: Dürig
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology; D049109:Cell Proliferation; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D039441:Integrin alpha4 / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000209:etiology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011379:Prognosis; D012307:Risk Factors; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D014183:Transplantation, Heterologous; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D017931:DNA Primers; D008562:Membrane Glycoproteins; D039441:Integrin alpha4; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1