Trisomy 12 chronic lymphocytic leukemia cells exhibit upregulation of integrin signaling that is modulated by NOTCH1 mutations

Blood. 2014 Jun 26;123(26):4101-10. doi: 10.1182/blood-2014-01-552307. Epub 2014 May 14.

Abstract

The leukocyte adhesion cascade is important in chronic lymphocytic leukemia (CLL), as it controls migration of malignant cells into the pro-survival lymph node microenvironment. Circulating trisomy 12 CLL cells have increased expression of the integrins CD11a and CD49d, as well as CD38, but the tissue expression of these and other molecules, and the functional and clinical sequelae of these changes have not been described. Here, we demonstrate that circulating trisomy 12 CLL cells also have increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and the adhesion molecule CD323. Notably, there was reduced expression of CD11a, CD11b, and CD18 in trisomy 12 cases with NOTCH1 mutations compared with wild type. Trisomy 12 cells also exhibit upregulation of intracellular integrin signaling molecules CALDAG-GEFI, RAP1B, and Ras-related protein ligand, resulting in enhanced very late antigen-4 [VLA-4] directed adhesion and motility. CD38 expression in CLL has prognostic significance, but the increased CD38 expression in trisomy 12 CLL cells must be taken into account in this subgroup, and the threshold of CD38 positivity should be raised to 40% for this marker to retain its prognostic value. In conclusion, trisomy 12 CLL cells exhibit functional upregulation of integrin signaling, with β2-integrin expression being modulated by NOTCH1 mutation status.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cell Movement / genetics
  • Chromosomes, Human, Pair 12 / genetics
  • Chromosomes, Human, Pair 12 / metabolism
  • Gene Expression Regulation, Leukemic*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Integrins / biosynthesis*
  • Integrins / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplastic Cells, Circulating / metabolism*
  • Neoplastic Cells, Circulating / pathology
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Signal Transduction*
  • Trisomy / genetics
  • Trisomy / pathology
  • Up-Regulation*
  • rap GTP-Binding Proteins / genetics
  • rap GTP-Binding Proteins / metabolism

Substances

  • Guanine Nucleotide Exchange Factors
  • Integrins
  • NOTCH1 protein, human
  • Neoplasm Proteins
  • RASGRP2 protein, human
  • Receptor, Notch1
  • RAP1B protein, human
  • rap GTP-Binding Proteins

Supplementary concepts

  • Chromosome 12, 12p trisomy