Latexin: A novel tumor suppressor in hematologic malignancies

Grant: ACS-178898
Award Amount: $99,768
PI: L.B. Schook, Y. Liang
Start Date: June 1, 2010
End Date: April 30, 2012

Leukemia is one of the leading causes of death in the US. It is characterized by the accumulation of non-functional, immature hematopoietic cells, which are derived from leukemia stem cells (LSCs). Mechanisms leading to the transformation of LSCs from normal hematopoietic stem cells (HSCs) are largely undefined, and both genetic and epigenetic changes resulting in the inhibition of tumor suppressor gene(s) and/or activation of oncogenes have been shown to play roles. Identification of molecules and mechanisms involved in malignant transformation, especially with respect to cancer stem cells, holds promise for cancer prevention, diagnosis, and therapy.

We have discovered in mice that a gene, Latexin (Lxn), is involved in the regulation of proliferation, apoptosis, self-renewal, and subsequently pool size, of normal hematopoietic stem cells (HSCs).  Previous studies showed that Lxn was highly homologous to Tazarotene-Induced Gene 1 (TIG1), which is down-regulated or absent in an extensive list of tumor types. We therefore hypothesize that Lxn is a potential tumor suppressor and plays a role in hematologic malignancies.

The goal of this project is to determine whether Lxn expression is altered in leukemic cells. Progenitor and stem cell-enriched CD34+CD38–cells (BD Pharmingen) in normal individuals and leukemia patients were sorted using a BD FACSVantage (Becton Dickinson), and real-time PCR was performed to measure Lxn mRNA expression. Our preliminary data showed that expression of Lxn was absent or significantly decreased in acute myeloid leukemia (AML) cells from three patients and in leukemia cell lines (K562, HL-60, KG-1, Jurkat, U937, SupB15, CCRF-CEM Molt4 and J45.01), indicating its potential role as a tumor suppressor.

Future projects will examine Lxn expression in other types of myeloid and lymphoid leukemia samples. We have a large variety of patient samples available including AML, chronic myeloid leukemia (CML), T cell prolympholeukem ia (PCTL), plasma cell leukemia (PCL), adult T cell lymphoma (ATLL), acute lymphoid leukemia (ALL, preB phenotype), and myelodysplastic syndromes (MDS).