The availability of tissue culture cell lines has made it possible to study the regulation of proliferation and differentiation of specific hematopoietic cell types and the effects on these cells of known or suspected mediators and modulators. It was found previously in this laboratory that retinoic acid (RA) is a potent inducer of terminal differentiation of the human promyelocytic cell line, HL-60, and the human monoblast- and monocyte-like cell lines, U-937 and THP-1. In addition RA was found to induce differentiation of fresh cells in primary culture of patients with acute promyelocytic leukemia. While retinoic acid alone is capable of inducing terminal differentiation, combinations of a physiological concentration of RA (10nM) and either cAMP inducing agents (e.g., cAMP, prostaglandin E, or cholera toxin) or the conditioned medium from either activated T-cells or human leukemic T-cell lines synergistically induced differentiation of HL-60. An activity called """"""""differentiation inducing activity"""""""" or DIA has been purified from these conditioned media and attempts are now being made to produce monoclonal antibodies against this protein. In addition to DIA, gamma-interferon also has differentiation inducing activity. However, polyclonal antibody against gamma-interferon does not neutralize DIA. Studies are now in progress to apply the results obtained in vitro with HL-60 to a transplantable HL-60 tumor carried in athymic nude mice. These studies should have applicability in the treatment of patients with some leukemias.
