Stam group

The main focus of the Stam group has always been MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (i.e. children <1 year of age), which represents a highly aggressive and difficult to treat type of childhood leukemia. Recently, however, we have expanded our focus by initiating research on high-risk types of pediatric acute myeloid leukemia (AML) characterized by MLL translocations or NUP98 gene fusions, in collaboration with Prof. dr. Michel Zwaan. For these specific ALL and AML patient groups we aim to 1. Understand the biology and (epi)genetics underlying a. leukemogenic transformation at pre-leukemic stages, and b. leukemia maintenance during full-blown overt leukemia, and c. disease relapse, 2. Unravel the molecular mechanisms underlying drug resistance and therapy failure, and develop therapeutic opportunities to circumvent adverse drug responses, and 3. Identify and pre-clinically validate novel therapeutic targets and innovative treatment strategies, using refined in vitro and in vivo model systems.

Group leader: Dr. Ronald Stam

Phone +31 (0 )88 972 76 72

Email R.W.Stam@prinsesmaximacentrum.nl

As the 5-year event free survival chances for patients diagnosed with MLL-rearranged acute lymphoblastic and myeloid leukemia, or NUP98-rearranged acute myeloid leukemia, still remain <40%, current therapeutic regimens clearly are not suitable for these specific patient groups, emphasizing the urgent need for more adequate treatment options for these children. Using various high-throughput screening approaches such as elaborate drug library screens, RNA and whole genome sequencing, CRISPR/Cas9 library screens, single-cell sequencing, microarray analyses, and protein array assays, we are continuously searching for novel therapeutic targets and innovative treatment strategies. Subsequently, refined in vitro and in vivo model systems are being used to validate the potential of identified therapeutic options, striving to provide sufficient pre-clinical evidence that allows the application of these newly found treatment opportunities in a clinical setting.

"No matter how rare the type of leukemia may be, every patient deserves the availability of competent therapeutic agents to help win the battle against their disease." Dr. Ronald Stam - Group leader

Grants

• Finding a cure for MLL-rearranged infant acute lymphoblastic leukemia (Cure2MLL) – Fight Kids Cancer/European Science Foundation grant (2023 - 2025)

• Modelling relapse occurrence following therapy-induced disease remission using patient-derived xenograft mouse models of MLL-rearranged acute lymphoblastic leukemia in infants - KiKa pilot grant (2022 - 2023)

• Identifying novel treatment strategies for infant MLL-rearranged acute lymphoblastic leukemia using comprehensive preclinical modeling - KWF (Dutch Cancer Society) grant (2019 - 2024)

• Identifying novel treatment strategies for MLL-rearranged acute myeloid leukemia using comprehensive preclinical modeling - KiKa pilot grant (2019 - 2020)

• Pre-clinical and early clinical assessment of Irinotecan as a highly potent agent against MLL-rearranged acute lymphoblastic leukemia in infants - KiKa grant (2017 - 2019)

• Characterizing the Role of Histone Deacetylase Family Members in MLL-rearranged ALL - KiKa grant (2016 - 2019)

Key publications

Stam RW, Schneider P, Hagelstein JAP, van der Linden MH, Stumpel DJPM, de Menezes RX, de Lorenzo P, Valsecchi MG, Pieters R. Gene expression profiling-based dissection of MLL-translocated and MLL-germline Acute Lymphoblastic Leukemia in infants. (2010) Blood 115(14):2835-2844. PubMed PMID: 20032505

Stumpel DJPM, Schneider P, van Roon EHJ, Boer JM, Lorenzo P, Valsecchi MG, de Menezes RX, Pieters R, Stam RW. Specific promoter methylation identifies different subgroups of MLL-rearranged infant Acute Lymphoblastic Leukemia, influences clinical outcome and provides therapeutic options. (2009) Blood 114(27):5490-5498. PubMed PMID: 19855078

Stumpel DJPM, Schneider P, Seslija L, Osaki H, Williams O, Pieters R, Stam RW. Connectivity mapping identifies HDAC inhibitors for the treatment of t(4;11)-positive infant acute lymphoblastic leukemia. (2012) Leukemia 26(4):682-692. PubMed PMID: 22015773

Spijkers-Hagelstein JA, Pinhanços SS, Schneider P, Pieters R, Stam RW. Chemical genomic screening identifies LY294002 as a modulator of glucocorticoid resistance in MLL-rearranged infant ALL. (2014) Leukemia 28(4):761-769. PubMed PMID: 23958920

Garrido Castro P, van Roon EHJ, Pinhanços SS, Trentin L, Schneider P, Kerstjens M, Te Kronnie G, Heidenreich O, Pieters R, Stam RW. The HDAC inhibitor panobinostat (LBH589) exerts in vivo anti-leukaemic activity against MLL-rearranged acute lymphoblastic leukaemia and involves the RNF20/RNF40/WAC-H2B ubiquitination axis. (2018) Leukemia 32(2):323-331. PubMed PMID: 28690313