Leukocyte-associated Ig-like receptor-1 prevents granulocyte-monocyte colony stimulating factor-dependent proliferation and Akt1/PKB alpha activation in primary acute myeloid leukemia cells.
The leukocyte-associated Ig-like receptor-1 (LAIR-1), a surface leukocyte receptor containing two immune receptor tyrosine-based inhibitory motif (ITIM) is expressed on acute myeloid leukemia (AML) blasts isolated from peripheral blood or bone marrow of 17 patients (2 M0, 3 M1, 5 M2, 2 M4 and 5 M5 according to French, American and British classification). Further, we provide evidence thatLAIR-1 engagement inhibits granulocyte-monocyte colony-stimulating factor (GM-CSF)-induced proliferation of AML blasts. Indeed, leukemia cells stimulated with GM-CSF were blocked in the G0/G1 phase of the cell cycle and underwent apoptosis within 4 days after the engagement of LAIR-1. Remarkably, LAIR-1 was functional also in AML blasts which do not express CD33, mainly M4 and M5. Importantly, the LAIR-1 ligation led to a strong inhibition of both GM-CSF receptor-mediated intracellular calcium increases, phosphorylation and activation of Akt1/protein kinase B alpha, a substrate of the phosphatidylinositol-3 kinase. This last inhibitory effect was prevented by a synthetic peptide spanning the ITIM portion of LAIR-1, suggesting the involvement of SHP-1 phosphatase in LAIR-1-mediated inhibitory signal. Altogether, these findings indicate that the engagement of LAIR-1 can down-regulate GM-CSF-mediated survival and proliferation of AML blasts, suggesting an additional therapeutic approach to the treatment of AML patients.
Zocchi
M R
MR
Laboratory of Tumor Immunology, Department of Internal Medicine, Scientific Institute San Raffaele, Milan, Italy.
Pellegatta
F
F
Pierri
I
I
Gobbi
M
M
Poggi
A
A
D015703:Antigens, CD / Q000502:physiology; D015214:Antigens, Differentiation, Myelomonocytic / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D011971:Receptors, Immunologic / Q000032:analysis / Q000502:physiology*; D063268:Sialic Acid Binding Ig-like Lectin 3
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D011518:Proto-Oncogene Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011971:Receptors, Immunologic; D063268:Sialic Acid Binding Ig-like Lectin 3; C108073:leukocyte-associated immunoglobulin-like receptor 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt