PDZD2 Is Required for Normal Erythropoiesis and Its 37-KDa Secreted Product, sPDZD2, Functions As a Soluble Tumor Suppressor in AML

PDZ domain-containing protein 2 (PDZD2) is expressed in normal hematopoietic stem and progenitor cells (HSPC), specifically HSC, MPP, and erythroid progenitors, however, it is almost universally lost through hypermethylation in acute myeloid leukemia (AML). PDZD2 encodes for a 300-kDa protein containing 6 PDZ domains. The full-length protein is cleaved in the cytoplasm in a caspase 3-dependent manner, and the C-terminal fragment containing PDZ domains 5 and 6 is secreted to the tissue microenvironment as a 37-kDa protein known as secreted PDZD2 (sPDZD2). sPDZD2 has been reported to function as a tumor suppressor in some solid tumors, including breast, prostate, and liver cancer. Thus, we hypothesized that PDZD2 is required for normal hematopoiesis and that sPDZD2 functions as a soluble tumor suppressor in the hematopoietic system. We first sought to determine if sPDZD2 is secreted to the bone marrow (BM) microenvironment. Using an ELISA to quantify sPDZD2 levels in BM plasma isolated from healthy donors (n=6) and primary AMLs (n=20), we confirmed its secretion by normal CD34+ HSPCs (NBM) and downregulation in AMLs (NBM: 169 ± 17.53 vs AML: 46.12 ± 6.70 ng/ml; p