Acute myeloid leukemia (AML) is the second most frequent leukemia diagnosed in children, and natural killer (NK) cells have clinically important antileukemic effects. Children with AML who either do not enter remission after induction chemotherapy or who relapse despite standard chemotherapy have an extremely poor prognosis. Although unrelated donor (URD) hematopoietic cell transplantation (HCT) can cure some of these patients, their probability of survival is less than 25%. Our long-term goal is to elucidate the determinants of beneficial alloreactivity of human NK cells in URD HCT for childhood AML. Our central hypothesis is that NK- cell effects are determined by the expression of activating and inhibitory receptors. Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) on donor NK cells will be the key focus of this proposal, because we have shown that the expression of KIRs significantly affects patient outcome, is minimally influenced by the donor HLA type, is highly variable among individuals with the same KIR gene content, and may be undetectable, even if genotyping indicates its presence. This project will take advantage of the availability of a prospective cohort of patients enrolled in Children's Oncology Group (COG) AAML05P1 study and will receive a uniform transplantation regimen. The following Specific Aims will be addressed:
Specific Aim 1. To assess NK-cell development after URD HCT in patients with poor prognosis AML. NK-cell reconstitution and receptor-acquisition pattern will be evaluated in 160 HCT recipients by blood tests using flow cytometry, RT-PCR, RQ-PCR, and cytotoxicity analyses. We hypothesize that NK-cell development after HCT is primarily affected by the compatibility of donor KIRs and recipient KIR-ligands and by the number of CD34+ cells and CD3+ T cells in the graft.
Specific Aim 2 : To define the relationship between the status of donor NK-cell receptor and patient outcomes after unrelated donor (URD) HCT in patients with poor prognosis AML. We will correlate the relationships between factors affecting NK receptor status and clinical events in 160 HCT recipients. The testable hypotheses are that clinical outcomes are better if there is KIR incompatibility between donor and recipient and if NK-cell reconstitution and receptor-acquisition occurs early after HCT. Relevance to public health: Natural killer cells are blood cells that have antileukemic properties. We will investigate these properties in patients with acute myelogenous leukemia (AML) who are enrolled on Children's Oncology Group (COG) studies and will undergo hematopoietic cell transplantation (HCT) and in their unrelated donors. Our goal is to optimize the pairing of unrelated donors and recipients of HCT, thereby improving survival of pediatric patients with AML who typically have a poor prognosis.
| Bari, Rafijul; Leung, Matthias; Turner, Victoria E et al. (2011) Molecular determinant-based typing of KIR alleles and KIR ligands. Clin Immunol 138:274-81 |
