Effect of retinoic acid and interferon alpha on granulocyte-macrophage colony forming cells in chronic myeloid leukemia: Increased inhibition by all- trans- and 13- cis-retinoic acids in advanced stage disease

Abstract

Granulocyte-macrophage colony forming units (CFU-GM) from patients with advanced stage chronic myelogenous leukemia (CML), i.e. in blastic crisis (BC) or accelerated phase (AP), were inhibited by all- trans-retinoic acid (tRA) approximately 1000-fold more potently than those from chronic phase (CP) CML patients (median ic 50 = 10 −9 M tRA for six CML-AP/BC cases vs > 10 −6 M tRA for seven CML-CP cases). A similar activity pattern was observed for the stereoisomer 13- cis-RA (cRA). There was no apparent correlation of CFU-GM retinoid sensitivity with cloning efficiency or other colony characteristics. Interferon alpha-2a (INFα) alone strongly inhibited CFU-GM growth in all four CML-AP/BC cases ( ic 50 ⩽ 250 IU/ml) and three out of seven CML-CP cases ( ic 50 ⩽ 500 IU/ml), but there was little or no interactive effect between various concentrations of tRA and INFα (50 IU/ml) on CFU-GM from either CML-AP/BC or CML-CP cases. These results suggest that CML-AP/BC CFU-GM have some intrinsic molecular alteration(s) which markedly enhances their responsiveness to tRA and cRA, which may be clinically exploitable.