Laboratory for Molecular Biology of Leukemia
"We try to understand the genetic complexity of leukemia, with the aim to use that information to develop novel treatment strategies."
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. While these children have a high chance of survival with current chemotherapy treatment, they suffer significant short and long term side effects caused by the treatment. My laboratory aims to study the genetic complexity of ALL so that more targeted therapies can be developed.
We have used next-generation sequencing to identify the spectrum of chromosomal rearrangements and mutations present in T-cell ALL, and we are using single-cell sequencing approaches to obtain a view on the heterogeneity in each case. Single-cell sequencing can provide information on the order of mutation acquisition, on the cell origin, and on the sensitivity of the different leukemia clones to chemotherapy or targeted treatment.
Using integrated ChIP-seq, ATAC-seq, RIME and RNA-seq approaches, we are defining how transcription factor deregulation and constitutive kinase signaling influence each other during leukemia development. We have documented direct cooperation between STAT5 (a transcription factor activated downstream of cytokine receptors and tyrosine kinases) and TLX1 or HOXA9 transcription factors, which are frequently ectopically expressed in T-cell ALL. Better insight in how transcription is deregulated in leukemia may provide new avenues for targeted therapy. New promising therapies are tested in vivo using our collection of ALL xenograft models.
- Cooperative enhancer activation by TLX1 and STAT5 in NUP214-ABL1/TLX1 positive T-ALL.
- HOXA9 cooperates with activated JAK/STAT signaling to drive leukemia development.
- The CCR4-NOT complex is a tumor suppressor in Drosophila melanogaster eye cancer models.
- A novel pro-T cell model system to study oncogene function defines the molecular basis of cooperation between TAL1 and Pten deletion in T-ALL.
- Single-cell sequencing to study the origin and the order of mutation acquisition in T-ALL.
- The second-generation exportin-1 inhibitor KPT-8602 demonstrates potent activity against ALL.
- Selective Presenilin 1 inhibition is effective to target T-ALL cells with NOTCH1 mutations and is associated with less toxicity compared to broad gamma-secretase inhibitors.
The work of Jan Cools is supported by: