EFFECTS OF FLT3 LIGAND ON HUMAN LEUKEMIA-CELLS .1. PROLIFERATIVE RESPONSE OF MYELOID-LEUKEMIA CELLS

The growth of cells in vitro and in vivo is regulated by several envir onmental signals among which growth factors (cytokines) figure promine ntly. FLT3 is a novel cytokine receptor with intrinsic ligand-stimulat ed (FLT3 ligand, FL) tyrosine kinase activity. Here, using a specific anti-FLT3 monoclonal antibody (McAb) and flow cytometry we determined the expression pattern of the receptor protein in 55 human leukemia-ly mphoma cell lines and in 20 primary samples from patients with acute l ymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). FLT3 rece ptor surface expression was found predominantly in pre-B cell, myeloid and monocytic cell lines and in pre-B-ALL and AML cells. FL was overe xpressed in baby hamster kidney cells producing a recombinant protein that was functional in receptor binding and signaling. Incubation with FL induced H-3-thymidine uptake-measured proliferation in some myeloi d cell lines and in 2/9 AML cases, The strongest proliferative respons e was seen in the two growth factor-dependent myeloid leukemia cell li nes MUTZ-2 and OCI-AML-5. Long-term substitution of the commonly used cytokines with FL sustained the continuous proliferation of these two cell lines suggesting that also upon permanent activation FLT3 can fun ction as a mitogenic signaling molecule. Despite the high density of F LT3 receptor expression on cultured and fresh pre-BALL cells, no proli feration could be stimulated in any of these specimens. Incubation wit h the anti-FLT3 McAb had agonistic proliferative effects in MUTZ-2 and OCI-AML-5; an anti-FL reagent blocked FL-stimulated proliferation. To summarize, we demonstrated that FL is effective in inducing prolifera tion of leukemic myeloid cells and that protein expression does not ne cessarily indicate an FL-responsive cell. While the present data clear ly demonstrate that FL might play a proliferative role in leukemogenes is, further studies are needed to clarify whether the signals provided by FL:FLT3 interaction are confined to a proliferation-inducing funct ion or whether maturational progression could also be elicited in cert ain cells.