Acute myeloid leukemia (AML) is the most common type of leukemia in adults with improving but still limited treatment possibilities. It arises as a result of malignant transformation of myeloid progenitor cells. Among the contributing genetic lesions, mutations in FMS-like tyrosine kinase 3 (FLT3) occur in approximately 30% of patients, mostly in the form of internal tandem duplications (ITD). FLT3 also is crucial in hematopoietic stem cell survival and differentiation. Thus, exploring the molecular mechanisms governing FLT-3 as well as FLT3-ITD related signaling pathways will not only help to identify therapeutic targets to improve AML management but also to better understand the regulation of hematopoietic stem cell differentiation and self-renewal.
The group led by Prof. H. Phillip Koeffler, Senior Principal Investigator at the Cancer Science Institute of Singapore, has been studying the role of an important adaptor protein, Lnk, in hematopoiesis and leukemia. Dr. Dechen Lin, a very talented post-doctoral fellow working with Prof. Koeffler, has shown that Lnk functions as a critical regulator of TPO-MPL and EPO-JAK-STAT signaling and hematopoiesis.
Very recently, they revealed that Lnk suppresses both FLT3- and FLT3-ITD-dependent signaling pathways involved in the proliferation and expansion of hematopoietic cells as well as related leukemic cells. Moreover, they identified the tyrosine residues 572, 591 and 919 of FLT3 as phosphorylation sites involved in direct binding to Lnk. This work has just been published online in BLOOD on 31 August, 2012.
This is the first study demonstrating the relationship between Lnk and FLT3, which suggests that alteration of Lnk expression levels may provide a unique therapeutic approach for FLT3-ITD-associated hematopoietic diseases.
De-Chen Lin1,2,*, Tong Yin2, Maya Koren-Michowitz2, Ling-Wen Ding1, Saskia Gueller3, Sigal Gery2, Takayuki Tabayashi2, Ulla Bergholz4, Julhash U. Kazi5, Lars Rönnstrand5, Carol Stocking4, and H. Phillip Koeffler1,2
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore;
2Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, USA;
3Department of Hematology and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany;
4Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
5Experimental Clinical Chemistry, Wallenberg Laboratory, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.