The angioregulatory cytokine network in human acute myeloid leukemia - from leukemogenesis via remission induction to stem cell transplantation

Acute myeloid leukemia (AML) is characterized by bone marrow accumulation of immature leukemic blast cells. Conventional AML treatment includes induction chemotherapy to achieve disease control, followed by consolidation therapy with conventional chemotherapy or allogeneic/autologous stem cell transplantation (allo/auto-SCT) to eradicate residual disease. Even younger patients receiving the most intensive treatment have a median, long-term, AML-free survival of only 45-50%, highlighting the need for new treatment strategies. The important role of the bone marrow cytokine network during disease development and treatment is suggested by several observations, including: (i) the increased microvascular density (MVD) in leukemic bone marrow, (ii) experimental evidence of cytokine-mediated crosstalk between leukemic and microvascular endothelial cells, (iii) the prognostic impact of angioregulatory cytokine levels both in patients receiving conventional chemotherapy and allo-SCT, and (iv) the experimental evidence for an antileukemic effect of cytokine inhibition in human AML. Several cytokines are constitutively released by human AML cells, including interleukins, chemokines, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and angiopoietins. However, the cytokine system constitutes a functional, interacting network, and recent evidence suggests that analysis of serum cytokine profiles rather than the analysis of single cytokines should be used for prognostic evaluation of AML patients. We will discuss the role of angioregulatory cytokines in leukemogenesis, including their direct effects on the leukemic cells, as well as their indirect contribution to leukemogenesis through angioregulation and crosstalk between leukemic and neighboring stromal cells. We shall also discuss the possibility of targeting angioregulatory cytokines as a part of the treatment strategy in leukemia.