Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome

• Published in: Blood Vol. 114; no. 27; pp. 5512 - 5521
• Main Authors: Luesink, Maaike, Pennings, Jeroen L.A., Wissink, Willemijn M., Linssen, Peter C.M., Muus, Petra, Pfundt, Rolph, de Witte, Theo J.M., van der Reijden, Bert A., Jansen, Joop H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.12.2009
• Subjects: Anti-Inflammatory Agents - pharmacology; Apoptosis - drug effects; Arsenic Trioxide; Arsenicals - pharmacology; Cell Differentiation - drug effects; Cell Line, Tumor; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Chemokine CCL24 - genetics; Chemokine CCL24 - metabolism; Chemokine CCL7 - genetics; Chemokine CCL7 - metabolism; Chemokines - genetics; Chemokines - metabolism; Dexamethasone - pharmacology; Enzyme-Linked Immunosorbent Assay; Gene Expression Profiling; Gene Expression Regulation, Leukemic - drug effects; Humans; Leukemia, Promyelocytic, Acute - genetics; Leukemia, Promyelocytic, Acute - metabolism; Leukemia, Promyelocytic, Acute - pathology; Oligonucleotide Array Sequence Analysis; Oxides - pharmacology; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Syndrome; Tretinoin - pharmacology; Tumor Cells, Cultured
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-02-204834

In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide can induce a differentiation syndrome (DS) with massive pulmonary infiltration of differentiating leukemic cells. Because chemokines are implicated in migration and extravasation of leukemic cells, chemokines might play a role in DS. ATRA stimulation of the APL cell line NB4 induced expression of multiple CC-chemokines (CCLs) and their receptors (> 19-fold), resulting in increased chemokine levels and chemotaxis. Induction of CCL2 and CCL24 was directly mediated by ligand-activated retinoic acid receptors. In primary leukemia cells derived from APL patients at diagnosis, ATRA induced chemokine production as well. Furthermore, in plasma of an APL patient with DS, we observed chemokine induction, suggesting that chemokines might be important in DS. Dexamethasone, which efficiently reduces pulmonary chemokine production, did not inhibit chemokine induction in APL cells. Finally, chemokine production was also induced by arsenic trioxide as single agent or in combination with ATRA. We propose that differentiation therapy may induce chemokine production in the lung and in APL cells, which both trigger migration of leukemic cells. Because dexamethasone does not efficiently reduce leukemic chemokine production, pulmonary infiltration of leukemic cells may induce an uncontrollable hyperinflammatory reaction in the lung.