Oncogenic Deregulation of Cell Adhesion Molecules in Leukemia

Abstract

Numerous cell⁻cell and cell⁻matrix interactions within the bone marrow microenvironment enable the controlled lifelong self-renewal and progeny of hematopoietic stem and progenitor cells (HSPCs). On the cellular level, this highly mutual interaction is granted by cell adhesion molecules (CAMs) integrating differentiation, proliferation, and pro-survival signals from the surrounding microenvironment to the inner cell. However, cell⁻cell and cell⁻matrix interactions are also critically involved during malignant transformation of hematopoietic stem/progenitor cells. It has become increasingly apparent that leukemia-associated gene products, such as activated tyrosine kinases and fusion proteins resulting from chromosomal translocations, directly regulate the activation status of adhesion molecules, thereby directing the leukemic phenotype. These observations imply that interference with adhesion molecule function represents a promising treatment strategy to target pre-leukemic and leukemic lesions within the bone marrow niche. Focusing on myeloid leukemia, we provide a current overview of the mechanisms by which leukemogenic gene products hijack control of cellular adhesion to subsequently disturb normal hematopoiesis and promote leukemia development.

Keywords: CAM; adhesion; integrin; leukemia; oncogene.

Figure 1

Structural and functional properties of the four major cell adhesion molecule families.

Figure 2

Adhesion molecule-mediated cell–cell interactions in the hematopoietic stem cell niche. Hematopoietic stem and progenitor cells (HSPCs) are able to assemble homotypic and heterotypic cell–cell and cell–matrix interactions (red arrows), via cell adhesion molecules (CAMs), such as VLA-4, VLA-5 and LFA-1, thereby regulating proliferation, self-renewal and differentiation. tpx, transplantation; rhG-CSF, recombinant human G-CSF.

Figure 3

RUNX1/ETO-induced CAM signature within the bone marrow microenvironment. The cell adhesion molecules PSGL-1, LFA-1, CD44, and VLA-4 have been described as target genes directly regulated by RUNX1/ETO [100,104,105,107]. Neutrophil elastase (NE) has been described as a RUNX1/ETO-repressed target gene [114].

Figure 4

Described and hypothesized mechanisms of oncogenic interference with adhesion molecule function. (A) Transcriptional deregulation of adhesion molecule expression by aberrant transcription factors (e.g., RUNX1/ETO [100] or TAL1) [51]. (B) Interference with cellular destruction of adhesion molecules through proteasomal degradation. (C) Activation of integrin receptors by co-receptors (e.g., the SDF1α/CXCR4/VLA4 axis) and modulators thereof (e.g., CEBPα) [89]. (D) Interference with the composition of the adhesion molecule complex. (E) Superactivation of pre-activated adhesion molecule signaling pathways (e.g., by receptor tyrosine kinases) [73]. ITG, integrin; RTK, receptor tyrosine kinase.