T-lineage acute lymphoblastic leukemia (T-ALL) accounts for 10-15% of childhood ALL, the most common form of childhood cancer. Prognostic indicators of patient outcome in T-ALL are few, and those currently identified are too weak or inappropriate for risk stratification. Since good biologic predictors of patient outcome in T-ALL do not exist, the utility of risk stratification strategies based on biologic predictors, a common and successful strategy for improving patient outcome in other types of leukemia, is not useful in T-ALL. In this R21 proposal, we hypothesize that ex vivo survival of T-ALL cells (T-lineage lymphoblasts) on bone marrow (BM) stromal cells is a discriminating predictor of patient outcome. Furthermore, we postulate that adhesion receptor defects alter survival of T-ALL cells on BM stroma and, when measured in a novel flow cytometry based assay, may also correlate with disease characteristics or patient outcome. In the first aim, we will test the hypothesis that ex vivo survival of T-lineage lymphoblasts predicts treatment outcome. We will use a novel cellular assay that we have recently established in our laboratory to examine ex vivo T-lineage lymphoblast survival. Ex vivo survival of T-lineage lymphoblasts will be correlated with event free survival (EFS, the primary endpoint) and slow early response (secondary endpoint, i.e. disappearance of blasts from the bone marrow during the first 14 days of therapy). In the second aim, we will test the hypothesis that adhesion receptor defects may correlate with T-ALL biology or patient outcome.
The second aim i s to employ a novel assay for detecting adhesion receptor activity on the surface of cells. This assay uses fluorescein-labeled small molecules that bind to the binding site of integrins LFA-1 or VLA-4. By using these compounds at a concentration equivalent to their affinity constant, we can detect the affinity state of the receptor as well as detect the affinity state conversion in real time, The affinity state of the receptor will be correlated with ex vivo survival, disease characteristics, and patient outcome as in Aim 1. Accomplishment of Aim 2 will provide an additional prognostic tool as well as provide novel insights into the biology of leukemia that can be pursued in future studies. Although aim 2 involves more risk than aim 1, its completion is likely to produce insightful and novel data about the importance of adhesion receptors in leukemia biology and cell survival. In addition, this novel assay format may be potentially valuable in a wide array of biologic and clinical studies. Identification of a strong predictor of patient outcome is important to improving therapy, since having good prognostic indicators will allow for risk-based treatment stratification. ? ?
| Winter, Stuart S; Jiang, Zeyu; Khawaja, Hadya M et al. (2007) Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 110:1429-38 |
