INTERACTION OF ACUTE-LEUKEMIA CELLS WITH THE BONE-MARROW MICROENVIRONMENT - IMPLICATIONS FOR CONTROL OF MINIMAL RESIDUAL DISEASE

There is increasing evidence for an interaction between acute leukemia cells and the microenvironment of the bone marrow. Blast cells from c ases of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) bind to cellular and extracellular matrix components of the bone marrow stroma. In AML, adhesion to stroma is mediated by the combined action of beta 1 (principally VLA-4) and beta 2 integrins, while in p recursor-B ALL VLA-4 and VLA-5 integrins play a major role. Adhesion m olecules such as CD31, CD44, non-beta 1, beta 2 integrins, growth fact or receptors such as c-kit, and other molecules are also likely to pla y a role. Binding of acute leukemia blasts to ligands on stroma has se veral pathophysiological consequences. Stromal contact is able to inhi bit programmed cell death (apoptosis) in a proportion of cases of both AML and ALL. In ALL, diffusible molecules derived from stroma appear to contribute. Marrow stroma also plays a part in regulating leukemic cell proliferation. While this is partly due to stromal production of hemopoietic growth factors, in soluble or transmembrane form or bound to extracellular matrix, signalling mediated directly by binding of ad hesion molecules on leukemic cells may also have a role. Contact of AL L biases with marrow fibroblasts is followed by migration of leukemic cells, utilizing VLA-4 and VLA-5 integrins, potentially allowing homin g of blasts to favourable microenvironmental sites, or controlling egr ess into the circulation. AML cells compete for stromal binding sites with natural killer cells and cytotoxic lymphocytes, which are known t o inhibit their clonogenic growth. We speculate that these complex int eractions between leukemic blasts, cellular and matrix components of s troma, and cytotoxic lymphocytes, play a critical role in determining the fate of small numbers of leukemic cells surviving after cytotoxic chemotherapy.