Human LAIR1 blocking peptide

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.

Background: Severe malarial anaemia (SMA) is a leading cause of childhood mortality in holoendemic Plasmodium falciparum regions. Methods: To gain an improved understanding of SMA pathogenesis, whole genome and transcriptome profiling was performed in Kenyan children (n= 144, 3-36 months) with discrete non-SMA and SMA phenotypes. Leukocyte associated immunoglobulin like receptor 1 (LAIR1) emerged as a predictor of susceptibility to SMA (P < 1 x10(-2), OR: 0.44-1.37), andwas suppressed in severe disease (-1.69-fold, P=0.004). To extend these findings, the relationship between LAIR1 polymorphisms [rs6509867 (16231C>A); rs2287827 (18835G>A)] and clinical outcomes were investigated in individuals (n= 1512, <5 years) at enrolment and during a 36-month longitudinal follow-up. Findings: Inheritance of the 16,231 recessive genotype (AA) increased susceptibility to SMA at enrolment (OR= 1.903, 95% CI: 1.252-2.891, P= 0.003), and longitudinally (RR= 1.527, 95% CI: 1.119-2.083, P= 0.008). Carriage of the 18,835 GA genotype protected against SMA cross-sectionally (OR = 0.672, 95% CI: 0.480-0.9439, P = 0.020). Haplotype carriage (C16231A/G18835A) also altered cross-sectional susceptibility to SMA: CG (OR = 0.717, 95% CI: 0.527-0.9675, P = 0.034), CA (OR = 0.745, 95% CI: 0.536-1.036, P = 0.080), and AG (OR = 1.641, 95% CI: 1.160-2.321, P = 0.005). Longitudinally, CA carriage was protective against SMA (RR = 0.715, 95% CI: 0.554-0.923, P = 0.010), while AG carriage had an additive effect on enhanced SMA risk (RR = 1.283, 95% CI: 1.057-1.557, P = 0.011). Variants that protected against SMA had elevated LAIR1 transcripts, while those with enhanced risk had lower expression (P < 0.05). Inheritance of 18,835 GA reduced all-causemortality by 44.8% (HR= 0.552, 95% CI: 0.329-0.925, P= 0.024), while AG haplotype carriage increased susceptibility by 68% (HR = 1.680, 95% CI: 1.020-2.770, P= 0.040). Interpretation: These findings suggest LAIR1 is important formodulating susceptibility to SMA and all-cause childhood mortality. (C) 2019 Published by Elsevier B.V.