Ivo Touw

Pathologenesis of congenital neurtopenia and secondary myeloid malignancies


Program leader: Ivo P. Touw, PhD

G-CSF receptor function in normal myeloid development and in myeloid disease 

Granulocyte colony-stimulating factor (G-CSF) is the major hematopoietic growth factor involved in the control of neutrophil development. G-CSF is applied on a routine basis in the clinic for treatment of congenital and acquired neutropenias. G-CSF activates a receptor of the hematopoietin receptor superfamily, the G-CSF receptor (G-CSF-R), which subsequently triggers multiple signaling mechanisms. Our aim is to understand how these mechanisms contribute to the responses of hematopoietic cells to G-CSF and how perturbations in intracellular signaling are implicated in various types of myeloid disorders. We specifically focus on the identification of mutations and rare polymorphisms in the G-CSF-R mutations in severe congenital neutropenia (SCN), myelodysplasia (MDS) and acute myeloid leukemia (AML) and their consequences for routing and signaling functions of the G-CSF-R (Fig. 1).

Figure 1. Intracellular domain of G-CSF receptor with major signaling mechanisms and cellular responses associated with different regions and tyrosine-based docking motifs. Most frequent mutations in severe congenital neutropenia truncate the C-terminal region of G-CSF-R, resulting in the loss of negative regulation by suppressor of cytokine signaling SOCS3 and receptor endocytosis. These acquired nonsense mutations are strongly associated with progression to acute myeloid leukemia.

Mechanisms underlying leukemic progression of congenital bone marrow failure syndromes
Congenital bone marrow failure syndromes such as severe congenital neutropenia often progress to acute myeloid leukemia. Our aim is to understand the multistep leukemic progression in these conditions. Our working hypothesis is that chronic genotoxic stress, e.g., caused by increased levels of reactive oxygen species (ROS), is not adequately dealt with by DNA repair mechanisms and is a key step in the pathogenesis of SCN/AML (Fig. 1). To identify critical genes and signaling mechanisms involved in leukemic progression, we use retroviral mutagenesis screens in mouse myeloid leukemia models and genetically modified mouse strains with specific DNA repair deficiencies.

Figure 2. Model for leukemic progression of severe congenital neutropenia. Critical sequential steps in this model involve (1) chronic genotoxic stress (perhaps caused by mutations in neutrophil elastase that are frequent in these patients) leading to premature senescence of primitive myeloid precursors; (2) accumulation of acquired mutations in regulatory genes including G-CSF-R, leading to escape from senescence and expansion of premalignant clones and (3) acquisition of additional genetic defects (Ras mutations, chromosome 7 abnormalities, etc) giving rise to myeloid leukemia.

Significance of murine retroviral mutagenesis for identification of disease genes in human acute myeloid leukemia
Retroviral insertion mutagenesis is a strategy to find novel cancer genes in mice. To explore its significance for human cancer, we have studied expression of potential disease genes identified in retroviral screens in murine leukemia in subgroups of human acute myeloid leukemia (AML) classified by gene expression profiling. Genes affected by virus integrations, but not randomly selected genes or genes located more distantly from virus integration sites, could be linked to specific gene expression profiles in AML. This information can be used to identify novel disease genes and regulatory networks involved in the pathogenesis of human AML. Erkeland SJ, Verhaak RGW, Valk PJM, Delwel R, Löwenberg B, Touw IP. Cancer Research (priority report), in press .