The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development

Nat Cell Biol. 2015 May;17(5):665-77. doi: 10.1038/ncb3158. Epub 2015 Apr 27.

Abstract

Conventional strategies are not particularly successful in the treatment of leukaemia, and identification of signalling pathways crucial to the activity of leukaemia stem cells will provide targets for the development of new therapies. Here we report that certain receptors containing the immunoreceptor tyrosine-based inhibition motif (ITIM) are crucial for the development of acute myeloid leukaemia (AML). Inhibition of expression of the ITIM-containing receptor LAIR1 does not affect normal haematopoiesis but abolishes leukaemia development. LAIR1 induces activation of SHP-1, which acts as a phosphatase-independent signalling adaptor to recruit CAMK1 for activation of downstream CREB in AML cells. The LAIR1-SHP-1-CAMK1-CREB pathway sustains the survival and self-renewal of AML stem cells. Intervention in the signalling initiated by ITIM-containing receptors such as LAIR1 may result in successful treatment of AML.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Amino Acid Motifs
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • RNA Interference
  • Receptors, Immunologic / deficiency
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Signal Transduction
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured
  • Young Adult

Substances

  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Receptors, Immunologic
  • leukocyte-associated immunoglobulin-like receptor 1
  • CAMK1 protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6