Linda Smit is in the division of Haematology of the VU University Medical Centre. The focus of the laboratory is on the identification of molecules that are specific for leukemic stem cells (LSCs) in Acute Myeloid Leukemia (AML) and Chronic Myeloid Leukemia (CML). After identification of these novel LSC specific molecules, AML and CML patient expression studies will be done to adequately assess the disease status which might help to give the most appropriate treatment. Expression of the identified molecules will facilitate the prediction of post-therapy relapse and most importantly it might identify novel specific drug targets, resulting in specific therapies for AML and CML LSCs. With the use of high throughput loss-of function screens with RNAi interference libraries, components will be identified that could result in novel highly specific drug targets in AML and CML. In addition, the use of RNAi screens are used to understand the characteristics of the LSC and the mechanism of acquired therapy resistance (of the LSC) in AML and CML.

The research focus of the Haematology department of the VU University Medical Centre is the LSC in AML and CML. It has been shown that the stem cell like phenotype of the LSC may account for their capability to escape conventional therapy and that it might be necessary to eradicate the LSC to cure leukemia. The haematology group has identified several specific LSC markers for AML and CML and additionally has shown that mechanism that are responsible for enhanced resistance to apoptosis are more prominent in more primitive cells of AML.

Linda Smit received her PhD in 1998 at the Immunology department of the Netherlands Cancer Institute in Amsterdam. In 1999 she started working as a postdoctoral fellow in the laboratory of Prof. Hans Clevers at the Hubrecht Laboratory in Utrecht where she worked on the involvement of Wnt signalling in the development of colon carcinoma. In 2004 she started a second postdoctoral fellowship at the Netherlands Cancer Institute in the laboratory of Prof. Rene Bernards. In the laboratory of Dr. Bernards, Dr. Smit has studied the characteristics and mechanism of drug resistance of breast cancer stem cells by the use of functional genomic approaches. Since May 2008 she is working at the Hematology department of the VU Medical Centre. The main research focus of Dr. Smit is on the identification of therapeutics for the treatment of leukemia. This includes exploiting large-scale siRNA library screening to determine factors that contribute to maintenance of the LSC in AML and CML (after therapy).

Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer. Carretero J, Medina PP, Blanco R, Smit L, Tang M, Roncador G, Maestre L, Conde E, Lopez-Rios F, Clevers HC, Sanchez-Cespedes M. Oncogene. 2007, 26(11):1616-1625.

van Rhenen A, van Dongen GA, Kelder A, Rombouts EJ, Feller N, Moshaver B, Stigter-van Walsum M, Zweegman S, Ossenkoppele GJ, Jan Schuurhuis G. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood. 2007, 110(7):2659-2666.

van Rhenen A, Moshaver B, Kelder A, Feller N, Nieuwint AW, Zweegman S, Ossenkoppele GJ, Schuurhuis GJ. Aberrant marker expression patterns on the CD34+CD38- stem cell compartment in acute myeloid leukemia allows to distinguish the malignant from the normal stem cell compartment both at diagnosis and in remission. Leukemia. 2007, 21(8):1700-1707.

van Rhenen A, Feller N, Kelder A, Westra AH, Rombouts E, Zweegman S, van der Pol MA, Waisfisz Q, Ossenkoppele GJ, Schuurhuis GJ. High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival. Clin Cancer Res. 2005,11(18):6520-6527.

van Stijn A, Feller N, Kok A, van der Pol MA, Ossenkoppele GJ, Schuurhuis GJ. Minimal residual disease in acute myeloid leukemia is predicted by an apoptosis-resistant protein profile at diagnosis. Clin Cancer Res. 2005,11(7):2540-2546.

LKB1 tumor suppressor protein: PARtaker in cell polarity. Baas AF, Smit L, Clevers H. Trends Cell Biol. 2004, 14(6):312-9.

Wnt activates the Tak1/Nemo-like kinase pathway. Smit L, Baas A, Kuipers J, Korswagen H, van de Wetering M, Clevers H. J Biol Chem. 2004, 279(17):17232-17240.

van Stijn A, van der Pol MA, Kok A, Bontje PM, Roemen GM, Beelen RH, Ossenkoppele GJ, Schuurhuis GJ. Differences between the CD34+ and CD34- blast compartments in apoptosis resistance in acute myeloid leukemia. Haematologica. 2003, 88(5):497-508.

Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, Alessi DR, Clevers HC. EMBO J. 2003, 22(12):3062-3072.