Mechanisms of acute promyelocytic leukemia cell infiltration and mobilization during ATRA therapy: new strategy for prevention of ATRA syndrome and additional chemotherapy.

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Differentiation-induction therapy with all trans retinoic acid (ATRA) is the first line therapy in acute promyelocytic leukemia (APL). Differentiation syndrome (DS) is the most serious adverse event during ATRA therapy. Further, although mobilization of APL cells into peripheral blood requires additional chemotherapy during ATRA therapy, the mechanism of the mobilization is unclear. In the current study, CXCL12 appeared to be a chemoattractant of APL cells. Treatment of APL cells with ATRA enhanced chmotaxis towards CXCL12. Increase of chemotaxis significantly associated with occurrence of DS and the requirement of additional chemotherapy. Activation of phospholipase C pathway appeared to be crucial for the chemotaxis. These results suggest that chomotaxis ability of APL cells toward CXCL12 is involved in the pathogenesis of DS and the requirement of chemotherapy during induction therapy with ATRA. Furthermore, specific signal targeted-therapy might contribute to prevent DS and additional chemotherapy.