Imbalance of c-MPL Isoform Promotes Tumorigenesis by Activating STAT-5 in Leukemic Cell Lines

Leukemia is a hematopoietic defect, involving complex molecular and cellular alterations, in which dysregulated signaling through hematopoietic receptors, including c-MPL (c-Myeloproliferative Leukemia), has been implicated. The function of c-MPL is mostly regulated by the crosstalk and stoichiometry of its different isoforms. Although expression of c-MPL in hematological disorders has been studied, the regulation of its isoforms and their balance, functional roles, and mechanisms of action in conditions such as acute and chronic leukemia and myeloproliferative neoplasms remain poorly understood. The association of c-MPL isoforms with leukemia cell proliferation and aggressiveness was examined by immunophenotyping, immunofluorescence, RT-PCR, Western blotting and clonogenic assay. This study demonstrates that an increase in the ratio of c-MPL-Full Length (FL)/c-MPL-Truncated (TR), the conserved isoforms of c-MPL, influences tumorigenic markers such as Ki67, Caspase-3, and BCL-2, thereby promoting aggressiveness in leukemic cell lines. Furthermore, we have observed that with an increase in the c- MPL-FL/c-MPL-TR ratio, STAT5 activation increases, promoting the proliferative state of leukemic cells, thereby revealing c-MPL isoforms as a therapeutic target for leukemia. In this work, we observed an increased c-MPL expression in leukemic cell lines, but cell proliferation is independent of total c-MPL expression. Our study demonstrates the regulatory role of c-MPL isoforms, particularly c-MPL-FL, in increasing cell proliferation in leukemia cell lines. This finding is a step towards developing c-MPL isoform as a therapeutic target for leukemic conditions such as acute and chronic leukemias and myeloproliferative neoplasms, but it needs further investigation for complete validation.