The role of STAT5 and KRAS in hematopoiesis and acute myeoloid leukemia

Fátrai S
Source: Other
Publication Date: (2010)
Issue: 0:0: Thesis
Research Area:
Immunotherapy / Hematology
Basic Research
Cells used in publication:
CD34+ cell, human
Species: human
Tissue Origin: blood
Chromosomal translocations or molecular abnormalities in hematopoietic stem cells can disrupt the normal process of self-renewal and differentiation, which can result in malignant transformation. A number of key transcription factors and signaling molecules have been identified that function aberrantly in leukemic cells. In this thesis we investigated the effects of STAT5 and KRAS on human hematopoietic stem cell selfrenewal and differentiation, and their potential role in leukemic transformation. Constitutive activation of STAT5 in CD34+ cord blood cells by retroviral transduction resulted in the upregulation of the membrane protein MUCIN1. Based on this information (chapter 2) we investigated the role of MUCIN1 in normal hematopoiesis as well as in primary AML cells. We demonstrated that 10% of the cord blood CD34+ cells were MUCIN1-positive. MUCIN1 mRNA expression was the highest in the CD34+/CD38-cell fraction. Experiments with cord blood CD34+/MUCIN1+ and CD34+/MUCIN1- cell populations revealed that stem/progenitor cells reside predominantly in the CD34+/MUCIN1+ fraction. To further study the role of MUCIN1 in hematopoiesis we stably overexpressed full-length MUCIN1 and a MUCIN1 isoform with a deleted extracellular domain (DTR) in cord blood CD34+ cells. In MS5 coculture assays a two-fold increase in expansion of suspension cells was observed, and LTC-IC frequencies and progenitor numbers were increased upon overexpression of MUCIN1 or DTR