CCL2/CCR2: push/pull for migration

In this issue of Blood, Luesink and colleagues report that in APL, the induction of massive production CC-chemokines (CCLs) and their receptors (CCRs) in APL cells by differentiating therapy with ATRA or ATO may play an important role in the development of the DS,¹  formerly known as retinoic acid syndrome.² 

The full-blown differentiation syndrome (DS) is characterized by unexplained fever, weight gain, dyspnea with interstitial pulmonary infiltrates, pleural or pericardial effusions, hypotension, and acute renal failure.²  However, the pathophysiology of DS is not fully understood, and detailed knowledge about its molecular mechanism remains largely unknown. Previously, it has been observed that differentiation therapy in acute promyelocytic leukemia (APL) (1) increases the release of inflammatory cytokines from differentiating APL cells,³  (2) increases the expression of cellular adhesion molecules on leukocytes,⁴  and (3) up-regulates specific chemokines.⁵  The simultaneous production of these proteins after exposure to all-trans retinoic acid (ATRA) may exacerbate the hyperinflammation observed in DS. The incidence of DS in patients receiving ATRA/arsenic trioxide (ATO) treatment has been reported to range from 2% to 27% with an associated mortality of about 2%.

The paper by Luesink et al in this issue of Blood presents in vitro evidence that chemokines may have a role in the development of DS.¹  Chemokines, together with their receptors, play a crucial role in directing the movement of mononuclear cells throughout the body, contributing to the pathogenesis of a variety of diseases.⁶  These investigators, using ATRA-stimulated of NB4 cells, were able to induce mRNA expression of multiple CC-chemokines (CCLs) and their receptors (CCRs), resulting in increased chemokine production in supernatant of these cells and increased chemotaxis. Two of these chemokines (CCL2 and CCL24) were up-regulated early and, despite the addiction of cycloheximide (a protein translation inhibitor), up-regulation of the mRNA expression was confirmed even though protein levels were not increased. This indicated that their induction was directly mediated by retinoic acid receptors. The addition of dexamethasone to ATRA did not inhibit chemokine induction in ATRA-stimulated NB4 cells. Moreover, as opposed to what was observed with NB4 cells, in primary leukemia cells derived from 5 newly diagnosed APL patients, only CCL2 was consistently up-regulated at mRNA and protein levels. Furthermore, increased levels of CCL2, CCL4, CCL7, and CCL24 were found in plasma of an APL patient with DS and not in 2 APL patients without DS. Finally, by adding ATO alone in NB4-cultured cells, only CCL2 and CCL7 were up-regulated more than 5-fold.

These results indicate that CCL2 and CCL7 are elevated in a single patient with DS studied and also in the NB4-cultured cells stimulated with ATRA and/or ATO. However, as only CCL2 was consistently up-regulated by ATRA addition at mRNA and protein levels in the primary leukemia cells derived from 5 newly diagnosed APL patients, it is this chemokine that may play an important role in the development of DS. CCL2 or monocyte chemoattractant protein 1 (MCP-1) is a potent agonist for monocytes, dendritic cells, memory T cells, and basophils.⁶  Moreover, when secreted from alveolar epithelial cells, it has an important role in the cell-to-cell interaction involved in the chemotactic transmigration of differentiated APL leukemic cells toward alveolar epithelial cells.⁷  Previous studies have indicated that IL-8³  and adhesion molecules⁴  may also have a role in DS. Because dexamethasone does not efficiently reduce leukemic chemokine production and pulmonary infiltration of leukemic cells may induce an uncontrollable hyperinflammatory reaction in the lung, the therapeutic use of chemokine-receptor antagonists may be a more efficient approach than the use of steroids to treat DS in APL. Among these chemokine-receptor antagonists, CCR2 (receptor for CCL2) and CXCR1 (receptor for IL-8) antagonists, used in phase 1 and 2 studies for treating rheumatoid arthritis and chronic obstructive pulmonary disease, respectively, are the most interesting. Despite the strength of in vitro experimental data, a potential limitation of this paper is that the studies are limited to only one APL patient with DS. Therefore, more APL patients with DS should be studied to evaluate more precisely the role of these chemokines in the pathophysiology of DS.

As in the setting of human migration,⁸  the chemokine and chemokine receptor production in APL treated with differentiation therapy may act as push (chemokine) and pull factors (chemokine receptors) for migration of leukemic cells from the bloodstream to the tissues, contributing to the development of DS. Moreover, the increased levels of CCL2 during differentiation therapy may become a marker of DS.