Ronald Stam obtained his PhD in 2006 at the Erasmus MC – Sophia Children’s Hospital (Rotterdam, the Netherlands), for his research on MLL-rearranged Acute Lymphoblastic Leukemia (ALL) in infants, supervised by Prof. dr. Rob Pieters. Upon acquiring his PhD, Ronald was appointed principal investigator at the Erasmus MC – Sophia Children’s Hospital, and initiated his infant ALL research group. During this period, Ronald has been an invited speaker at the annual meetings of the American Society of Hematology (ASH) and the International Society of Pediatric Oncology (SIOP). Furthermore, Ronald was rewarded the “Basic Science Award” at the 34th annual meeting of the International Society of Pediatric Oncology (SIOP), and the “World Care Benelux – KiKa Award” for groundbreaking research in pediatric oncology. Ronald joined the Princess Máxima Center for Pediatric Oncology in September 2016, where he will continue his work on MLL-rearranged infant ALL together with his enthusiastic research group.
The Stam Group focuses on MLL-rearranged acute leukemias. The presence of chromosomal translocations involving the MLL gene represents the cytogenetic hallmark of Acute Lymphoblastic Leukemia (ALL) in infants (<1 year of age). MLL-rearranged infant ALL is a highly aggressive malignancy, which is largely (if not solely) driven by inappropriate epigenetic events. Despite tremendous advances in the treatment of pediatric ALL in general, the even-free survival chances of MLL-rearranged infant ALL remains a dismal 30-40%. As this type of leukemia is notoriously characterized by cellular drug resistance towards conventional chemotherapeutic drugs, and further treatment intensification is not possible due to treatment-related toxicity, the development of more efficient treatment approaches reached an impasse. Nonetheless, if there is one thing we learned after more than a decade of dedicating our research to search for more adequate treatment options, it will be that this aggressive type of leukemia responds remarkably well to epigenetic-based therapeutics. For instance, we were the first to characterize the DNA methylome of MLL-rearranged ALL and subsequently showed that DNA demethylating agents efficientlyinduce leukemic cell death. Likewise, we pioneered the notion that HDAC inhibition highly effectively targets MLL-rearranged ALL cells, and provided insights into the mechanism underlying these anti-leukemic effects. Meanwhile, we, and others, have explored the potency of other types of epigenetic-based drugs, including inhibitors of BET and DOT1L, as well as inhibitors of methylation such as DZNep and Neplanocin. All of these different types of epigenetic-based drugs show promising results against MLL-rearranged leukemia, suggesting that the use of epigenetic-based therapies certainly seem essential to improve the clinical outcome for patients diagnosed with this aggressive and difficult-to-treat malignancy. Therefore our research momentarily largely aims to
- Providing sufficient in vitro and in vivo (i.e. using xenotransplantation mouse models) pre-clinical evidence and rationales for the use of various epigenetic-based drugs in near-future clinical trials,
- Fine-tune the use of epigenetic-based drugs and study the most beneficial strategies of implementing these agents into existing treatment protocols,
- Study epigenetic plasticity by which MLL-rearranged ALL cells eventually develop resistance towards epigenetic-based drugs by epigenetic re-routing of there dependencies when under continuous selective pressure of such medications,
- Dissect all of the inappropriate (epi)genetic events that drive this type of leukemia.
Apart from these main topics, we are currently developing a genuine mouse model of MLL translocation driven transformation and leukemogenesis, together with our long-term collaborators Prof. dr. Pablo Menedez and Dr. Clara Bueno at the Josep Carreras Leukemia Research Institute, Barcelona, Spain. Moreover, we very recently initiated the exploration of tumor heterogeneity in MLL-rearranged infant ALL using single-cell sequencing techniques, in collaboration with Prof. dr. Frank Holstege (Princess Máxima Center for Pediatric Oncology).
- Stam, R.W., den Boer, M.L., Schneider, P., Nollau, P., Horstmann, M., Beverloo, H.B., van der Voort, E., Valsecchi, M.G., de Lorenzo, P., Sallan, S.E., Armstrong, S.A. and Pieters, R.: Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia. Blood 106:2484-2490 (2005).
- Spijkers-Hagelstein, J.A., Mimoso Pinhanços, S., Schneider, P., Pieters, R., and Stam, R.W.: Src kinase-induced phosphorylation of annexin A2 mediates glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia. Leukemia 27(5):1063-71 (2013).
- Stam, R.W., Schneider, P., Hagelstein, J.A.P., van der Linden, M.H., Stumpel, D.J.P.M., de Menezes, R.X., de Lorenzo, P., Valsecchi, M.G., and Pieters, R.: Gene expression profiling-based dissection of MLL-translocated and MLL-germline Acute Lymphoblastic Leukemia in infants. Blood 115(14):2835-44 (2010).
- Stumpel, D.J.P.M, Schneider, P., van Roon, E.H.J., Boer, J.M., Lorenzo, P., Valsecchi, M.G., de Menezes, R.X., Pieters, R., and Stam R.W.: Specific promoter methylation identifies different subgroups of MLL-rearranged infant Acute Lymphoblastic Leukemia, influences clinical outcome and provides therapeutic options. Blood 114(27):5490-8 (2009).
- Stumpel, D.J., Schneider, P., Seslija, L., Osaki, H., Williams, O., Pieters, R., and Stam, R.W.: Connectivity mapping identifies HDAC inhibitors for the treatment of t(4;11)-positive infant acute lymphoblastic leukemia. Leukemia 26(4):682-92 (2012).
- Garrido Castro, P., Van Roon, E.H.J., Mimoso Pinhancos, S.S., Schneider, S., Kerstjens, M.J.B., Willekes, M., Pieters, R., Stam, R.W.: The histone deacetylase inhibitor Panobinostat (LBH589) exerts anti-Leukaemic activity in a MLL-rearranged ALL xenograft mouse model. Blood 124:3709 (2014); ASH abstract. [full paper submitted].
- Ronald Stam (PI)
- Patricia Garrido Castro (post-doc)
- Pauline Schneider (PhD-student)
- Priscilla Wander (PhD-student)
- Sandra Mimoso Pinhanços (Senior technician)