Linda Smit, PhD
The overall aim of the group of Linda Smit is the identification of efficient therapeutic strategies that eliminate leukemia stem cells (LSCs) and/or minimal residual disease (MRD), thereby improving future clinical therapies and increasing leukemia patient survival rates.
The identification and pre-clinical validation of therapeutic targets specifically eliminating leukemic stem cells
One of the aims of the group of Linda Smit is to identify mechanisms differentially utilized in LSCs and normal hematopoietic stem cells (HSCs) that might be used as therapeutic targets. We have identified several specific LSC markers, including microRNAs, for acute myeloid leukemia (AML) that can be efficiently targeted to specifically eliminate LSCs (De Leeuw et al. Cancer Res. 2014; De Leeuw et al. Leukemia 2016; Verhagen Cell Reports 2018).
One of the pathways strongly associated with stem cell biology and cancer is the Wnt signaling pathway. Currently, we are studying whether therapeutic intervention of the Wnt signaling pathway is a promising strategy to eliminate LSCs and/or reduces MRD.
Targeting the transcriptome and epigenome to eliminate therapy resistant leukemia (stem) cells
The second area of research of the group of Linda Smit is heterogeneity in therapy response due to aberrant transcriptional regulation and epigenetic function that is associated with MRD and LSCs. We aim to identify epigenetic/transcriptional characteristics including vulnerabilities of chemotherapy resistant AML (stem) cells by the genetic and epigenetic characterization of MRD, and by exploiting large-scale CRISPR-Cas9 screening approaches. This knowledge will be utilized to guide the validation of potential treatment strategies in pre-clinical studies ex vivo and in a patient derived xenograft (PDX) leukemia mouse model.
Mechanisms associated with sensitivity to retinoic acid-driven differentiation in leukemia
Acute promyelocytic leukemia (APL) is the only AML subtype that is successfully treated with all-trans retinoic acid (ATRA) and low doses arsenic trioxide (ATO). ATRA forces APL cells into differentiation, thereby sensitizing them for ATO-induced killing, and leading to almost 100% of cures. Unfortunately, among other subtypes of AML, ATRA-based treatment has so far not been very effective. We have previously identified that AML cells overexpressing EVI-1 are sensitive to ATRA (Verhagen et al. Blood 2016), and subsequently we initiated a proof of principle clinical trial treating EVI-1+ patients at relapse with the combination of chemotherapy and ATRA. Furthermore, we aim to identify mechanisms that are associated with sensitivity to retinoic acid (RA)-based differentiation therapy in AML cells. This knowledge might reveal response biomarkers but might also reveal factors that upon targeting induce sensitivity for RA-driven differentiation.
The Smit lab received funding from World Wide Cancer Research (2008), CCA-VICI (2011, 2014, 2016), Stichting Leukemie (2012), the Dutch Cancer Society (KWF) (2014 and 2015), and through collaborations with the pharmaceutical companies Novartis and Neomed. Moreover, a VUmc Innovation grant was obtained in 2017.
Members of the group
Noortje van Gils Msc | PhD student
Fedor Denkers, Ing | Senior Technician
Linda Smit graduated in Medical Biology from the Free University, Amsterdam in 1992 and received her PhD in 1998 at the department of Immunology of the Netherlands Cancer Institute in Amsterdam on the subject of “Signaling pathways in B lymphocytes”. 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 postdoctoral fellowship at the Netherlands Cancer Institute in the laboratory of Prof. Rene Bernards. In the Bernards lab, Dr. Smit has studied the characteristics and mechanism of drug resistance of breast cancer stem cells by the use of functional genomic approaches. From 2008, she became Assistant Professor at the Hematology department of the VU Medical Centre, where she is leading her independent research group, working on the identification of therapeutics for the treatment of AML. Moreover, she is leading (together with hematologist Dr. J.J.W.M Janssen) the molecular diagnostic team of the department of Hematology at Amsterdam UMC, location VUmc.
IGFBP7 induces differentiation and loss of survival of human acute myeloid leukemia stem cells without affecting normal hematopoiesis.
Cell Reports 2018: 25(11):3021-3035.
Verhagen HJ., van Gils N., Martiañez T., van Rhenen A., Rutten A., Denkers F., de Leeuw DC., Smit M., Tsui M-L., de Vos Klootwijk LLE., Menezes RX., Çil M., Roemer MGM., Vermue E., Heukelom S., Zweegman S., Janssen JJWM, Ossenkoppele GJ., Schuurhuis GJ. and Smit L.
Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all trans retinoic acid.
Blood. 2016: 127(4):458-463.
Verhagen HJ, Smit MA, Rutten A, Denkers F, Poddighe PJ, Merle PA, Ossenkoppele GJ, Smit L.
MicroRNA-551b is highly expressed in hematopoietic stem cells and a biomarker for relapse and poor prognosis in acute myeloid leukemia.
Leukemia. 2016: 30(3):742-746.
de Leeuw DC, Verhagen HJMP, Denkers F, Kavelaar FG, Valk PJM, Schuurhuis GJ, Ossenkoppele G. and Smit L.
Attenuation of microRNA-126 expression that drives CD34+38- stem/progenitor cells in acute myeloid leukemia leads to tumor eradication.
Cancer Research 2014: 74(7):2094-105.
de Leeuw DC, Denkers F, Olthof MC, Rutten AP, Pouwels W, Schuurhuis GJ, Ossenkoppele GJ, Smit L.
An integrated genomic approach identifies that the PI3K/AKT/FOXO pathway is involved in breast cancer tumor initiation.
Oncotarget. 2016; 7(3):2596-2610.
L. Smit, K. Berns, K. Spence, W.D. Ryder, N. Zeps, M. Madiredjo, R. Beijersbergen, R. Bernards and R.B. Clarke.