Klin Padiatr 2004; 216 - 55
DOI: 10.1055/s-2004-828600

Activation of the HIF-1 pathway in childhood ALL

S Wellmann 1, E Moderegger 1, A Zelmer 1, W Griethe 1, M Guschmann 1, G Henze 1, K Seeger 1
  • 1Departments of Pediatric Oncology and Hematology, Nephrology and Medical Intensive Care, and Pathology, Charité, Medical University at Berlin, Germany

Hypoxia-inducible factor-1 (HIF-1) is the key regulator of adaptive responses to reduced oxygen availability, including erythropoiesis, angiogenesis and energy metabolism.

Recently we demonstrated by immunohistochemistry that the oxygen regulated component of HIF-1 (HIF-1α) is overexpressed in clusters of leukemic cells in bone marrow (BM) specimens of childhood acute lymphoblastic leukemia (ALL) and absent in biopsies of normal BM. Half the HIF-1α positive ALL biopsies exhibited coexpression with vascular endothelial growth factor (VEGF), an important pro-angiogenic HIF-1 target gene. Comparing the genomic response to hypoxia of two human B-cell precursor leukemic cell lines, one HIF-1α-competent, REH, with a HIF-1α-deficient, Z-33, led to the identification of the Wilms' tumor gene Wt1 to be a new HIF-1 target.

These findings together give evidence for an important role of HIF-1 in the BM of ALL. They show that leukemic cells may activate different mechanisms to develop more resistant subclones, able to cope with microenvironmental selection pressure.

Supported by the Deutsche José Carreras Leukämie-Stiftung (DJCLS-R03/16)