T-lineage acute lymphoblastic leukemia (T-ALL) arises from malignantly transformed progenitors in the bone marrow (BM) microenvironment. Patient outcome in T-ALL remains one of the worst among childhood leukemias. In order to improve patient outcome, there are two principal needs: 1.) development of prognostic markers for better risk stratification, and 2.) identification of new targets for pharmaceutical intervention. This proposal addresses both of these needs. In this proposal, we will couple our previous work with BM stroma-supported growth of T-ALL cells and our gene microarray analysis in order to identify novel prognostic markers and new therapeutic targets. Our underlying premise is that tumor survival is dependent on signaling pathways, communicated in large part through cell-cell contact, that stimulate growth, angiogenesis, or the production of anti-apoptotic factors, all of which help sustain some aspect of tumor cell growth, spread, and survival. The """"""""setting"""""""" in which these cellular interactions take place is often termed the microenvironment. In recent years, an understanding has developed that the microenvironment sustains leukemia cell growth. Because of the genetic alterations in the leukemia cell, the response of the leukemia cell to the microenvironment or the response of the microenvironment to the leukemia cell may be different from a normal cell counterpart. Thus, targeting the microenvironment for drug therapy has gained considerable interest, including small cell carcinoma, multiple myeloma, and other hematopoietic tumors. With the hypothesis that stroma-supported T-ALL cell survival may be predictive of treatment outcome coupled with our extensive experience in microarray analysis and studying receptors involved in cell-microenvironment, we postulate that genetic and functional differences in cell surface receptors exist on T-ALL cells between patients with good and bad outcome. We will identify novel prognostic factors as well as potential mechanisms of leukemia cell survival. After validation of prognostic assays and markers, we will focus our studies on determining a better understanding of microenvironmental ligands and cellular regulators of stroma-dependent T-ALL proliferation. We obtained R21 funding previously with the objective of obtaining the preliminary data and publications presented in this proposal. The R21 that we obtained (in response to PA-01-010) is only extendable under new R01 funding which this proposal represents. Our previous studies examined the samples available in a retrospective manner with tissue bank samples in order to generate the preliminary data and manuscripts necessary for this prospective trial. We have exhausted samples available to us from retrospective studies, but have generated data with sufficient significance to justify this prospective study. The data from this proposal will also be used in a non-overlapping aim as part of a SPECS proposal from the Children's Oncology Group in June. The SPECS proposal will focus on microarray analysis of precursor B-ALL and adult AML, but data from this proposal will be contributed to the aim focused on novel methods of bioinformatic analysis. In addition, we will share this data with Dr. Tom Look at the Dana Farber Cancer Center in order to correlate his genetic findings in his T-ALL Zebra fish model with our human studies.
