Background

Self-renewal, proliferation and differentiation are characteristics of haematopoiesis through which all cellular components of the blood are generated. The mechanism behind it is composed of a complex and tightly regulated signalling network, which is still poorly understood. Through a process termed leukaemogenesis, the regulatory units of this signalling network are hijacked leading to aberrant proliferation, stem cell like self-renewal and block differentiation of blood cells, which may result in haematopoietic malignancies such as acute myeloid leukaemia (AML).

Method

Phosphoinositides are pivotal signalling lipids, which orchestrate proliferation and differentiation, in addition to many other physiological aspects of the cell. Especially the phosphoinositide 3-kinase (PI3K) mediated pathways have been directly linked to carcinogenesis and AML in particular. However, a comprehensive study of all phosphoinositide modulators in haematopoiesis and leukaemogenesis has not been performed.

Results

Therefore, in this work, a lentivirus short hairpin (shRNAi) library targeting all 90 human phosphoinositide modulators, predominantly consisting of kinases and phosphatases, is transduced into human leukaemia cell lines as well as normal and leukaemic primary human bone marrow cells.

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Conclusion

In vitro and in vivo screens will potentially identify novel regulators of proliferation, differentiation and self-renewal in haematopoiesis and leukaemogenesis, which if druggable could be exploited in chemotherapy of AML.