High Frequency of Adhesion Defects in B-Lineage Acute Lymphoblastic Leukemia

Abstract

Aberrant proliferation, differentiation, and/or migration of progenitors observed in various hematological malignancies may be caused by defects in expression and/or function of integrins. In this study, we have developed a new fluorescent beads adhesion assay that facilitates flow cytometric investigation of lymphocyte function-associated antigen 1 (LFA-1)– and very late activation antigen-4 (VLA-4)–mediated functional adhesion in B-lineage acute lymphoblastic leukemia (ALL) of both the CD10− and CD10+ (leukemic) cell population within one blood or bone marrow sample. Surprisingly, of the 20 B-lineage ALL patients investigated, 17 contained a leukemic cell population with LFA-1– and/or VLA-4–mediated adhesion defects. Five patients contained CD10+ cells that did not exhibit any LFA-1–mediated adhesion due to the lack of LFA-1 surface expression. The CD10+ cells from 10 ALL patients expressed LFA-1 that could not be activated by the phorbol ester phorbol 12-myristate 13-acetate (PMA), whereas the CD10− cells expressed a functional LFA-1. Seven patients contained CD10+ cells that expressed a PMA-unresponsive form of VLA-4. The PMA unresponsiveness of the integrins LFA-1 and VLA-4 expressed by the CD10+ cells may be due to mutations in the integrins itself, in protein kinases, or in other intracellular molecules involved in integrin adhesion. These data clearly demonstrate the importance of investigating integrin function in addition to integrin surface expression. The strikingly high frequency (85%) of adhesion defects in ALL could suggest a causal relationship between integrin-mediated adhesion and B-lineage ALL.

Constitutive integrin activation on tumor cells contributes to progression of leptomeningeal metastases1

“…Several studies suggest that the inside-out signaling of integrins in tumor cells can be dysregulated, which can lead both to adhesion defects due to integrin inactivity and to increased adhesion caused by constitutive integrin activation. Geijtenbeek et al (1999) demonstrated a L b 2 integrin and a 4 b 1 integrin-mediated adhesion defects in leukemic cells isolated from bone marrow of patients with B-lineage acute lymphoblastic leukemia. Trusolino et al (1998) found that a v b 3 integrins on thyroid carcinoma were highly active and enriched at focal contacts, mediating tight adhesion, whereas these integrins were in a latent state on normal thyroid cells, which could not form cytoskeletal connections and promote cell adhesion.…”

Lentivirus-Mediated RNA Interference of DC-SIGN Expression Inhibits Human Immunodeficiency Virus Transmission from Dendritic Cells to T Cells

“…Fluorescent-bead adhesion assay. The fluorescent-bead adhesion assay was performed as previously described (25). Carboxylate-modified TransFluor-Spheres (488/645 nm; 1.0 m; Molecular Probes, Eugene, Oreg.)…”

“…Carboxylate-modified TransFluor-Spheres (488/645 nm; 1.0 m; Molecular Probes, Eugene, Oreg.) were coated with ICAM-3, monomeric HIV gp120, or Mycobacterium tuberculosis-derived mannose-capped lipoarabinomannan (ManLAM) as described previously (25,26). Fifty thousand cells were preincubated or not with anti-human DC-SIGN neutralizing MAb AZN-D2 (20 g/ml) or mannan (1 mg/ml; Sigma) for 45 min at 37°C.…”

“…5A) or DC-SIGNnegative DCs (Fig. 5B), we used a well-established fluorescentbead adhesion assay (23,25). Beads coated with HIV-1 gp120, M. tuberculosis cell wall component ManLAM, or ICAM-3 were incubated with cells stably expressing siRNAs.…”

Enhancing Antitumor Efficacy of Chimeric Antigen Receptor T Cells Through Constitutive CD40L Expression

“…31 Avoiding immunosurveillance through the downregulation of cell surface proteins (HLA Class I, costimulatory molecules, and/or adhesion molecules) is often employed by tumors to avoid elimination. 6,32,33 Apoptotic resistance can also occur with the loss of the Fas-death receptor on the surface of malignant cells. 34 To counteract this, CD40L mediates the upregulation of costimulatory molecules (CD80 and CD86), adhesion molecules (CD54, CD58, and CD70), HLA molecules (HLA Class I and HLA-DR) and facilitate apoptosis through the Fas/FasL pathway on malignant B-cell tumors.…”