Interdependence of oncogenic and epigenetic mechanisms in T-cell lymphoma.
Anaplastic large cell lymphoma (ALCL) is a highly malignant type of Non-Hodgkin’s T cell lymphoma in which chromosomal translocation leads to the expression of a fusion oncoprotein Tyrosine Kinase - Nucleophosmin/Anaplastic Lymphoma Kinase or NPM/ALK.
Dr. Wasik showed that NPM/ALK positive cancer cells have a selective loss of STAT5A, a tumor suppressor protein and a reciprocal inhibitor of NPM/ALK. (U4592)
NPM/ALK, acting through STAT3 transcription factor, selectively inhibits expression of STAT5a gene. Induction of STAT5a expression, either by gene transduction or application of DNA methyltransferase inhibitor to reverse the gene silencing, results in the inhibition of NPM/ALK expression and, consequently, death of the malignant cells.
The invention also provides a method to diagnose malignancy and monitor patient’s response to therapy by analysis of the degree of DNA methylation of the gene encoding for Stat5a or its analog, their mRNA, or protein.
Dr. Wasik also demonstrated that NPM/ALK induces the expression of immunosuppressive protein CD274, also known as PD-L1 or B7-H1 through STAT3. (V4957)
This invention provides methods for inhibiting an oncogenic protein or its down-stream effector to suppress expression of a cell-surface protein (PDL-1) involved in inhibiting immune response against malignant cells thereby enhancing the immunogenicity of a cell. The invention includes inhibitors of function or expression of oncogenic ALK tyrosine kinase and/or other oncogenic proteins and their effectors such as STAT3 responsible for induction of expression of CD274 or its functional immunosuppressive equivalent. This approach may represent an attractive (and not mutually exclusive) alternative to inhibiting CD274 and similar immunosuppressive with antibodies.
In addition, Dr. Wasik developed transformed CD4+ T cells by expressing NPM-ALK in normal human CD4+ T lymphocytes.
The NPM-ALK CD4 transformed cells become immortalized and display morphology and immunophenotype of patient derived anaplastic large-cell lymphomas. This is the first method to succeed in immortalizing these cells and the first to transform normal human cells of any kind using a well-defined single oncogene relevant to human disease.
Combined, these results demonstrate the relevance of targeting NPM-ALK or its downstream effectors as a potential immuno-onco-therapeutic approach. Given their uniqueness, these NPMALK transformed normal human CD4+ T cells may also be used to study therapeutic strategies aimed at prevention of cancer development.