target menu
... / ... / ... / Researchers / Ivo Touw
 

Ivo Touw

Leukemia predisposition syndromes

The cancer genome sequencing projects have provided important insights into the genetic complexity and clonal architecture of leukemia. An issue that is inadequately resolved by studying the “end-stage” tumors concerns the timing of the acquired defects, acknowledging the strong causal relationship between initiating driver mutations that cause a premalignant state and the subsequent defects that result in the progression to an overt malignancy. Severe congenital neutropenia (SCN), Shwachman Diamond Syndrome and Fanconi anemia are bone marrow failure syndromes characterized by a high risk of malignant transformation. We study these cancer predisposition syndromes because they provide attractive experimental and clinical models to elucidate the sequential cellular, genetic and epigenetic events in leukemic progression and to test the feasibility of targeting early drivers to prevent malignant transformation of these conditions.
One specific focus of our research is on the dysfunction of the membrane receptor for granulocyte colony stimulating factor (G-CSF), a seminal cytokine for neutrophil production. Previously, we discovered that nonsense mutations truncating the C-terminal region of this receptor (G-CSFR) are frequently acquired in SCN patients receiving G-CSF therapy and that these mutations herald progression to acute myeloid leukemia (AML). We have generated mouse models and patient-derived induced pluripotent stem cell lines to study the consequences of G-CSFR truncations and loss of G-CSF specific signaling functions on neutrophil development. We have established that intracellular trafficking of G-CSFR is pivotal for its balanced signaling output, a process that is severely affected by the G-CSFR truncations found in SCN/AML. More recently, we have embarked on genome-editing technologies to study the functional consequences of the sequential genomic abnormalities associated with the progression of SCN towards AML.