Van Leeuwen group

In ALL, treatment response is to a large part determined by the (cyto)genetic context, which has led to the implementation of risk-adapted therapies based on specific genetic abnormalities. By focusing on the molecular mechanisms that contribute to therapy resistance in distinct high risk ALL subtypes, we can develop novel, more personalized treatment strategies aimed at preventing (or curing) relapse.

Research direction

Deletions and mutations affecting lymphoid transcription factor IKZF1 are associated with poor outcome in BCP-ALL. We have recently shown that loss of IKZF1 function promotes resistance to glucocorticoid-induced apoptosis. In addition, we observed that deletion of IKZF1 affects the response to specific antimetabolites, both in cell line models and patient-derived xenografts. We are exploring how loss of IKZF1 affects metabolic handling of these drugs and we are using drug synergy studies to identify agents that overcome these resistance mechanisms.

Aims:

1. To obtain detailed insight into how metabolic changes associated with loss of IKZF1 function affect response to therapy

2. To identify small molecule inhibitors that can be used to overcome resistance to synthetic glucocorticoids or antimetabolites in IKZF1 deleted ALL

Tumor suppressor p53 is the most frequently mutated gene in human cancer, but with only 3% of leukemias showing loss of p53 at diagnosis, ALL is an exception to this rule. Although the incidence rises to 12% at relapse, the role of p53 in therapy resistance, and as a consequence, its prognostic value has long been overlooked.

Since the pro-apoptotic effects of most cytotoxic therapies require p53, loss of p53 function compromises the response to many anti-leukemic agents. We recently showed that this resistance is not limited to the classical chemotherapeutic agents, but extends to antibody-drug-conjugates and CAR-T therapies that are currently used to salvage relapsed patients. This means that there is an urgent need for novel treatment strategies to eradicate p53 deficient leukemic cells.

Research direction

We have generated isogenic cell line models of TP53 wildtype, knockout and hotspot knock-in mutations and used these cells in CRISPR- and drug screens to identify vulnerabilities that can be exploited. We found that in contrast to DNA damaging agents, many metabolic drugs retain their therapeutic effect in p53 deficient cells. We noticed that these drugs activate cell death mechanisms other than apoptosis, thereby circumventing the need for p53. Current studies focus on enhancing therapeutic efficacy of such metabolic therapies.

Aims:

1. Enhancing the therapeutic efficacy of targeting nucleotide metabolism

2. Exploiting metabolic vulnerabilities that induce p53 independent cell death

Asparaginase (ASNase) is a key component in the treatment of ALL. This bacterially-derived enzyme acts primarily by depletion of asparagine from the blood. As lymphocytes and leukemic blasts are selectively dependent on the exogenous supply of asparagine, exposure to ASNase leads to a cessation of growth and the induction of cell death. This selective dependency on amino acids is not unique to leukemia nor limited to asparagine. We are currently exploring the therapeutic efficacy of methionine restriction in ALL and other tumor types

Research direction

Methionine, in addition to being the amino acid encoded by the start codon and is therefore used in every protein , is a key precursor for several metabolic pathways. We found that different tumor types rely on the availability of methionine for different reasons. A subtype of leukemia  characterized by the KMT2A rearrangement requires methionine as a precursor for s-adenosyl-methionine (SAM) which serves as methyl donor for the epigenetic modifications that drive this leukemia subtype. Conversely, while neuroblastoma cells, a type of solid tumor, also rely on exogenous supply of methionine, it is not SAM that is rate limiting. Reverse genetic CRISPR screens have pointed us to other pathways that serve as the Achilles heel when neuroblastoma are challenged with methionine restriction. These pathways are currently being explored.

Aims

1. Optimize the therapeutic efficacy of methionine restriction in ALL and other tumor types

2. Explore the use of enzymatic methionine depletion strategies as therapeutic option

T-Cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive hematologic malignancy, representing 15% of ALL cases in both children and young adults. While outcomes of pediatric T-ALL have improved, with 5-year event-free survival rates approaching 85%, cure rates in relapsed/refractory T-ALL (R/R T-ALL) are only about 50%, despite the broad use of allogeneic hematopoietic stem cell transplantation. Unfortunately T-ALL patients have not yet benefited from the recently developed immunotherapies that are very successful in the treatment of B-ALL.  Therefore there is a clear unmet need for the development of alternative treatment strategies.

Research direction

The most prominent oncogenic drivers of T-ALL, such as NOTCH activation or loss of the tumor suppressors PTEN and FBXW7, result in constitutive activation of the MYC oncogene. Although long considered undruggable, the first MYC targeting therapies have shown promising results in solid tumors. We used several screening techniques, including drug screens and phospho-proteomics in cell lines and patient derived xenografts and showed that the by-proxy targeting of Myc through the inhibition of pathways that drive Myc expression is an effective strategy to eradicate T-ALL cells. 

Aims

1. Identify and optimize Myc targeting strategies in T-ALL.

T-cell lymphoblastic lymphoma (T-LBL) is a malignancy of immature T-cells in children and young adults. In children, T-LBL accounts for a quarter of the non-Hodgkin lymphomas. During the last decade, several genetic risk factors have been identified, but most did not result in clinically relevant risk groups. We recently discovered gene fusions involving NOTCH1. These T-LBL patients with NOTCH1 fusions have a cumulative incidence of relapse of 67% and an overall survival of 10-20%. Since this T-LBL subgroup appears to represent the majority of relapses, upon which salvage rates are extremely poor, this group can be considered very high risk. Currently, it is unknown why NOTCH1 fusions (in contrast to NOTCH1 DNA mutations) are associated with an extremely poor outcome, and better therapeutic options that lead to sustainable remission, are currently lacking.

Research direction

We aim to unravel the underlying mechanisms of resistance to standard therapy in NOTCH1 fusion-positive T-LBL. For this, we will make cell line as well as PDX models to study which currently used drugs are still effective and identify novel potential targets for treatment of this T-LBL subgroup.

Aims

1. Generate and compare cell line-based and patient-derived xenograft models of NOTCH1 fusion-positive T-LBL cases with.

2. Investigate the mechanisms driving tumor development and therapy failure in NOTCH1 fusion-positive T-LBL for different fusion partners.

3. Explore novel therapeutic options for NOTCH1 fusion-positive T-LBL.

1. Butler M, van der Meer LT, van Leeuwen FN. Amino Acid Depletion Therapies: Starving Cancer Cells to Death. Trends Endocrinol Metab. 2021;32(6):367-81.

2. Butler M, van Ingen Schenau DS, Yu J, Jenni S, Dobay MP, Hagelaar R, et al. BTK inhibition sensitizes acute lymphoblastic leukemia to asparaginase by suppressing the amino acid response pathway. Blood. 2021;138(23):2383-95.

3. Butler M, Vervoort BMT, van Ingen Schenau DS, Jongeneel L, van der Zwet JCG, Marke R, et al. Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways. Front Oncol. 2022;12:905665.

4. Cox WPJ, Dautzenberg NMM, Dekker L, Klenovsek T, Cornel AM, van Hoesel M, et al. Loss of p53 impairs death receptor expression and confers resistance to CD19 CAR T-cell therapy in BCP-ALL. Blood Neoplasia. 2025;2(1):100060.

5. Cox WPJ, Evander N, Van Ingen Schenau DS, Stoll GR, Anderson N, De Groot L, et al. Histone deacetylase inhibition sensitizes p53-deficient B-cell precursor acute lymphoblastic leukemia to chemotherapy. Haematologica. 2024;109(6):1755-65.

6. Tee T, Ruiter TJJ, Wu S, Zhang W, Schenau DVI, Rodionova M, et al. S-adenosylmethionine addiction confers sensitivity to methionine restriction in KMT2A-rearranged acute lymphoblastic leukemia. Haematologica. 2025;110(11):2620-34.

7. Vervoort BMT, Butler M, Grunewald KJT, Schenau D, Tee TM, Lucas L, et al. IKZF1 gene deletions drive resistance to cytarabine in B-cell precursor acute lymphoblastic leukemia. Haematologica. 2024;109(12):3904-17.

• Van Leeuwen Group (with Kuiper group) : KWF 10072: Breaking therapy resistance in IKZF1 deleted Acute Lymphoblastic Leukemia (2017-2021)

• Van Leeuwen Group (with Kuiper Group): KWF 11049: Improving asparaginase therapy response in acute lymphoblastic Leukemia by targeting pre-B cell receptor signaling (2019-2023)

• Kuiper group (with van Leeuwen group): KWF 12482: Mechanisms of hypermutation in relapsed acute lymphoblastic leukemia in children and implications for treatment (2019-2023)

• Van Leeuwen group: KiKa333: Improving antimetabolite therapies for IKZF1 deleted Leukemia (2019-2020)

• van Leeuwen group (with Stam Group) KWF 14253: Improving therapy response by targeting onine methionine metabolism in MLLr leukemia. (2022-2026)

• Van Leeuwen group KWF 14659: Improving nucleoside-based therapies for (pediatric) Acute Leukemias (2023-2027)

• Butterfly Cofund: Amino Acid depletion therapies for (relapsed) T cell Acute Lymphoblastic Leukemia (2023-2027)

• Fight Kids Cancer : ALLTogether team science – development of a preclinical testing platform to improve outcomes for drug resistant T-cell Acute Lymphoblastic Leukemia (2024-2027)

• Kuiper and van Leeuwen group KWF 17132: Tackling the Toughest: Therapeutic Strategies for High-Risk NOTCH1 Fusion-Driven T-Lymphoblastic Lymphoma