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Background: Leukaemia is a hematopoietic defect, and the development of this condition has a correlation with the hematopoietic receptor c-MPL. The function of c-MPL is mostly regulated by the crosstalk and stoichiometry of the different isoforms of c-MPL. Although expression of c-MPL in hematological disorders has been studied, the regulation of the isoforms, their balance, and the mechanism of action in conditions like acute and chronic leukaemias and myeloproliferative neoplasms need to be revealed to develop c-MPL as a therapeutic target for leukaemia cases. Methods: The association of c-MPL isoforms with increased tumorigenesis in leukaemia cells was examined using various molecular and cell biology techniques. The significance of the work depends on the statistical analysis of the experimental and technical triplicates. Results: The severity of the leukemic condition directly depends on the increased expression ratio of MPL-FL/MPL-TR. Furthermore, we have observed that with an increase in the MPL-FL/MPL-TR ratio, STAT5 activation increases to promote the transition of HSC from the G0 state to the HSC proliferative state, leading to an increase in the severity. Conclusion: Through this work, we have observed increased c-MPL expression in cells with hematopoietic disorders, but the severity of the condition is independent of the total MPL expression. Our study also provides compelling evidence for the regulatory role of c-MPL isoforms, particularly MPL-FL, in increasing disease severity in blood cancers. This finding is a significant step towards developing c-MPL as a therapeutic target for leukemic conditions like acute and chronic leukaemias and myeloproliferative neoplasms, but it needs a large-scale validation using AML patient samples.