Functional inactivation of tumor suppressors plays an important role in malignancy. Many tumor suppressors normally interface with the cell cycle machinery and form part of its exquisite control mechanism. Loss of these controls can lead to unrestricted proliferation and impaired differentiation, both of which are characteristic of acute myeloid leukemia. EKLF (Erythroid Kr?ppel Like Factor;KLF1) is a zinc finger hematopoietic transcription factor that is absolutely critical for the erythroid lineage. Our recent studies have also revealed an unexpected role of EKLF as an inhibitor of megakaryopoiesis, suggesting a novel function of this transcription factor in lineage commitment during hematopoiesis. EKLF inhibits cellular proliferation and induces endogenous expression of the cell cycle inhibitor p21. As a result, we hypothesize that human EKLF may play a role in hematopoietic malignancy consistent with that of a tumor suppressor, and this exploratory proposal will evaluate this idea by two aims. In the first, we will use an antibody that recognizes human EKLF protein to analyze human normal and leukemic tissue and cell samples for the presence/absence of EKLF protein, and determine whether its expression correlates with a specific malignant subtype. In the second, the sequence of the complete human EKLF transcription unit will be compared between normal bone marrow and a number of human leukemic cell lines and malignant primary cells to see if EKLF is mutated in any of these lines. Functional tests of any variant EKLF proteins that are discovered will follow both of these aims and will also provide a basis for future experiments that extend beyond the timeline of this exploratory grant. Successful attainment of the aims in this proposal will determine whether mutated EKLF/KLF1 plays a role in leukemia, thus providing a novel biomarker, and will direct future applicability towards the most clinically relevant samples.
Tumor suppressors play an important role in preventing malignancy. EKLF, a critical zinc finger hematopoietic transcription factor, has antiproliferative properties consistent with that of a tumor suppressor. As a result, our test hypothesis is that EKLF is playing an unappreciated role as a tumor suppressor, and that its dysregulation can contribute or lead to human leukemia.
|Gnanapragasam, Merlin Nithya; Crispino, John D; Ali, Abdullah M et al. (2018) Survey and evaluation of mutations in the human KLF1 transcription unit. Sci Rep 8:6587|
|Jaffray, Julie A; Mitchell, W Beau; Gnanapragasam, Merlin Nithya et al. (2013) Erythroid transcription factor EKLF/KLF1 mutation causing congenital dyserythropoietic anemia type IV in a patient of Taiwanese origin: review of all reported cases and development of a clinical diagnostic paradigm. Blood Cells Mol Dis 51:71-5|