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

Abstract

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. IntroductionAcute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosomal translocation, which fuses the promyelocytic leukemia (PML) gene on chromosome 15 to the retinoic acid receptor-␣ (RARA) gene on chromosome 17. This translocation results in blockage of terminal granulocytic differentiation at the promyelocytic stage. 1,2 Treatment with high dosage of the RARA ligand all-trans retinoic acid (ATRA) relieves this blockage, resulting in terminal differentiation of the APL blasts. Presently, standard therapy for patients with newly diagnosed APL consists of a combination of ATRA and anthracycline-based chemotherapy, which results in the induction of a complete remission in more than 90% of the patients and a 5-year overall survival rate of more than 80%. [3][4][5][6][7][8][9][10][11] In addition, arsenic trioxide (ATO) treatment has been shown to be highly effective in relapsed APL patients and has also been used successfully as a single agent or in combination with ATRA in newly diagnosed APL patients. [12][13][14][15][16][17][18][19][20][21] Despite the high cure rates, induction mortality is a still a problem in APL. In a large series of 732 APL patients who received ATRA plus idarubicin, induction mortality was 9%. The most common causes of death were hemorrhage, infection, and the differentiation syndrome (DS), formerly known as retinoic acid syndrome. 22 DS is reported in 2.5% to 31% of the APL patients who receive induction therapy with ATRA and/or ATO. [5][6][7]10,14,16,19,20,[23][24][25][26][27][28][29][30] DS is not observed during consolidation o...

Tissue transglutaminase contributes to the all-trans-retinoic acid–induced differentiation syndrome phenotype in the NB4 model of acute promyelocytic leukemia

“…Chemoattractive effect of ATRA-treated wild-type, virus control, and TG2-KD NB4 cell supernatants on white blood cells was evaluated using transwell polycarbonate inserts (6.5-mm diameter) with 5-m pores (Costar Corning) and carried out as described previously. 9 …”

“…7,8 Recently published results showed that infiltrating differentiating APL cells enhance migration of leukemic cells into the lung by the massive chemokine induction (eg, CCL2/MCP-1, CCL3/MIP-1a, CCL22/MDC, CCL24/MPIEF-2) provoked by ATRA treatment and pulmonary infiltration of APL cells induce an uncontrollable hyperinflammatory reaction in the lung. 9 NB4 is a well-characterized human promyelocytic leukemia cell line isolated and established from an APL patient. 10 ATRA induces terminal differentiation of these immature leukemic promyelocytes into granulocytes.…”

FNDC3B is another novel partner fused to RARA in the t(3;17)(q26;q21) variant of acute promyelocytic leukemia

“…It has been suggested that ligand-activated PML-RARA directly induces chemokine expression in differentiating APL cells, thereby triggering DS development. 9,10 Because FNDC3B-RARA is a potent transcriptional activator at pharmacological ATRA doses, it may be possible that the hyperactivated RARA signaling during ATRA therapy causes chemokine overproduction and early DS in our patient, who lacks risk factors for DS including high white blood cell counts, abnormal serum creatinine levels, and FLT3-internal tandem duplication.…”

“…Eight months after starting maintenance therapy with ATRA/methotrexate/ 6-mercaptopurine, the disease relapsed and cytogenetic studies showed clonal evolution with 45,X,-Y,der(1) t(1;8)(q42;q21),t(3;17)(q26;q21), t(10;13)(p11.2;q12) [11]/46,XY [9]. Exome sequencing identified a germ line variant in the mismatch repair gene MSH3 that might underlie the genomic instability (supplemental Figure 1, available on the Blood Web site).…”

Chemotherapy Toxicity in Patients with Acute Leukemia

“…The APL Differentiation Syndrome or Retinoic Acid Syndrome is mediated by endothelial inflammation and vascular leak that occurs when leukemic blasts suddenly differentiate into mature granulocytes and adhere to pulmonary endothelium. The differentiation syndrome occurs in approximately 25% of patients with APL treated with these agents (Luesink et al, 2009;Montesinos et al, 2009). Diagnosis should be suspected clinically in the presence of dyspnea, unexplained fever, weight gain, peripheral edema, unexplained hypotension, acute renal failure or CHF, but particularly by a chest radiograph demonstrating interstitial pulmonary infiltrates or pleuropericardial effusion.…”