Table 1.

Classification of β3 integrin ligands and an overview of the importance ligands, their important functions and their integrin binding; for additional details see [9] and the Gene database [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40].

Ligand	Integri Binding	Function of the Ligand in Human Acute Myeloid Leukemia (AML)	Key References
ADAM family members	αVβ3	ADAMTS-13, see von Willebrand factor (vWF) below.
Androgens	αVβ3	A recent study described improved survival of elderly patients when androgens maintenance treatment was combined with intensive chemotherapy.	[14]
BSP	αVβ3	Bone sialo protein (BSP). No known effect in AML.
Collagen	α10β3	Collagen IV promotes the migration and adhesion of primary human AML cells, MMP-9 is also increased. Collagen and collagen IV is present in human bone marrow. It is not known whether binding to integrins contributes to these effects or whether other receptors are responsible (e.g., the diskoid domain receptor 1).	[15]
COMP	αVβ3	Cartilage oligomeric matrix protein(COMP) This mediator is synthesized by osteoblasts and may thus be expressed in the bone marrow niches.	[16]
Connective tissue growth factor	αVβ3, αIIbβ3	Connective tissue growth factor (CTGF) is expressed in bone marrow stromal cells; it is regarded as a regulator of adipocyte differentiation and may influence leukemogenesis both through direct effects on the AML cells and through indirect effects on AML-supporting stromal cells. AML cells induce its expression in bone marrow mesenchymal cells.	[17,18]
Cyr61	αIIbβ3, αVβ3	Cystein-rich 61(Cyr61) is released by stromal cells, it is released as a matricellular protein and it increases the proapoptotic effects of mitoxantrone in AML-stromal cell cocultures.	[19]
Del-1	αVβ3	The secreted glycoprotein Developmental endothelial locus-1 (Del-1) is expressed endothelial cell, becomes associated with extracellular matrix or cell surfaces and regulates hematopoiesis in the bone marrow stem cell niche.	[20]
Fibrillin	αVβ3	Murine studies have demonstrated that the extracellular matrix protein, fibrillin, is expressed in the bone marrow and functions as a regulator of normal hematopoiesis.	[21]
Fibrinogen	αIIbβ3, αVβ3	The plasma fibrinogen levels at the time of diagnosis seem to have a prognostic impact and are associated with an adverse outcome in AML patients. This impact is not caused by increased early mortality, but it is not known whether this long-term effect is caused by a direct effect of fibrinogen on the AML cells. Both soluble and solid-phase fibrinogen induces Syk signaling in human megakaryoblastic cell lines.	[13,22]
Fibronectin	αIIbβ3, αVβ3	Experimental studies suggest that AML cell adhesion to fibronectin increase leukemia cell proliferation, accelerate S-phase entry and cause accumulation of the cell cycle inhibitor CDC25A. This CDC25A accumulation was caused by decreased degradation. Activation of PI3K-Akt-mTOR seemed to be important for this adhesion-dependent growth enhancement. Fibronectin adhesion inhibited the proliferation of normal CD34+ bone hematopoietic cells.	[23]
ICAM-4	αVβ3, αIIbβ3	Intercellular adhesion molecule-4 (ICAM-4) is expressed by erythroid cells and seems important in erythropoiesis, but it is not known whether it is important in AML.	[24]
L1	αVβ3, αIIbβ3	L1 is expressed by human monocytes and may thus be expressed in the bone marrow stem cell niches.	[25]
MFG-E8	αVβ3, αVβ5	The Milk fat globule-EGF-factor 8 protein (MFG-E8) is expressed and released by bone marrow macrophages and is thus present in the AML cell microenvironment.	[26]
MMP-2	αVβ3	Matrix metalloprotease 2 (MMP-2) is constitutively released by primary human AML cells for most patients and is involved in AML cell migration; it may even be important for the extracellular migration of leukemic cells. An adverse prognostic impact of constitutive MMP-2 release has been suggested.	[27,28,29]
Osteopontin	αVβ3	Monocytic differentiation in human AML cells seems to be associated with increased expression of both ITGαV and osteopontin. High osteopontin serum levels seem to be associated with an adverse prognosis in human AML, but this impact differs among patients and is most clearly seen for patients with intermediate risk factors.	[30,31,32]
PCAM	αVβ3	Mesenchymal stem cells express Platelet cell adhesion molecule (PCAM); this ligand is thus expressed in the bone marrow stem cell niches where leukemic stem cells locate.	[33]
SPARC	αVβ3?	Secreted-Protein-Acidic-Cysteine Rich (SPARC) Seems to induce β3-catenin signaling at least in subsets of human AML.	[34]
Thyroid hormones	αVβ3	A matched case-control study with 28 children/patients with AML showed that extreme Thyroid stimulating hormone (TSH) levels, both high and low at neonatal screening, were associated with decreased risk of AML	[35]
Trombospondin	αVβ3, αIIbβ3	Thrombospondin induces apoptosis in AML cell lines and also in primary human AML cells, but this effect may be due to ligation of CD36. The effect is antagonized by thrombopoietin, a mediator that is often increased in AML patients receiving intensive chemotherapy.	[36,37]
Vitronectin	αIIbβ3, αVβ3	Adhesion of Mixed lineage leukemia-Eleven-nineteen lysine-rich leukemia (MLL-ELL) murine myeloid progenitor cells to vitronectin activates/phosphorylates β3 integrins and Syk kinase.	[38]
vWf	αVβ3, αIIbβ3	ADAMTS-13 is essential for maintaining the keeping normal sized of the vWF; it cleaves the multimer into smaller forms. Low plasma levels of ADAMTS-13 seems to be associated with an adverse outcome in human AML, but it is not known whether this is due to an effect of ADAMTS-13/vWF directly on the AML cells or whether it represents a secondary reactive mechanism.	[39,40]