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C-fms expression correlates with monocytic differentiation in PML-RARα+ acute promyelocytic leukemia

Leukemia volume 17, pages 98–113 (2003)Cite this article

Abstract

We have investigated the expression of the M-CSF receptor (c-fms) in 16 freshly isolated acute promyelocytic leukemias (APL) expressing the PML/RARα fusion protein. In parallel, we evaluated the capacity of these cells to differentiate along the granulocytic and monocytic pathways. c-fms was constitutively and constantly expressed in all cases sensitive in vivo to all-trans retinoic acid (ATRA) and its expression was further potentiated following in vitro induction with ATRA. Furthermore, gel-shift analysis of APL cells showed elevated levels of PU.1 binding activity to the M-CSF receptor promoter, particularly after ATRA stimulation. Interestingly, the rise of PU.1 binding activity as well as of PU.1 levels after ATRA treatment was significantly higher in APL patients exhibiting monocytic maturation, as compared to those that did not undergo monocytic differentiation. A variable proportion of ATRA-induced APL cells exhibited monocyte-like morphology and immunophenotype: the proportion of monocytic cells was consistently increased by combined treatment with ATRA and diverse hematopoietic growth factors cocktails, which always comprised M-CSF. Monocytic cells originating from in vitro ATRA-induced maturation of APL cells derive from the leukemic clone as suggested by two lines of evidence: (1) monocytic cells harbor the 15;17 translocation; (2) monocytic cells possess Auer bodies. The c-fmsbright leukemic blasts preferentially showed the capacity for monocytic differentiation as compared to the c-fmsdim/− subset: indeed, enforced expression of c-fms into NB4, a PML/RARα+ cell line, favored the onset of monocytic maturation. Finally, low c-fms expression was observed in an APL relapsing patient resistant to ATRA, as well as in an APL case with t(11;17), PLZF/RARα+. These observations indicate that PML/RARα+ APL blasts are bipotent for differentiation through both neutrophilic and monocytic lineages, whereby monocytic differentiation is linked to c-fms expression and stimulation.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Istituto Superiore di Sanità, Rome, Italy

    R Riccioni, E Saulle, S Militi, N M Sposi, M Gualtiero, C Peschle & U Testa

  2. Department of Cellular Biotechnology and Hematology, University ‘La Sapienza’, Rome, Italy

    N Mauro, M Mancini, D Diverio & F Lo Coco

  3. T Jefferson University, Kimmel Cancer Center, Philadelphia, PA, USA

    C Peschle

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  1. R Riccioni
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Riccioni, R., Saulle, E., Militi, S. et al. C-fms expression correlates with monocytic differentiation in PML-RARα+ acute promyelocytic leukemia. Leukemia 17, 98–113 (2003). https://doi.org/10.1038/sj.leu.2402812

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