The association of ICAM-1 Exon 6 (E469K) but not of ICAM-1 Exon 4 (G241R) and PECAM-1 Exon 3 (L125V) polymorphisms with the development of differentiation syndrome in acute promyelocytic leukemia

Abstract

The use of all trans-retinoic acid (ATRA) is the basis of treatment of acute promyelocytic leukemia (APL) and represents the paradigm of differentiation therapy. In general, ATRA is well-tolerated but may be associated with a potentially lethal side-effect, referred to as retinoic acid or differentiation syndrome (DS). The cellular and molecular mechanisms of DS are poorly understood and involve changes in the adhesive qualities and cytokine secretion of leukemic cells during ATRA-induced differentiation. As leukocyte extravasation is a key event in DS pathogenesis, we analyzed the association between the polymorphisms at Exon 4 (G241R) and Exon 6 (E469K) of ICAM-1 and Exon 3 (L125V) of PECAM-1 genes with DS development in APL patients treated with ATRA and anthracyclines. DS was diagnosed in 23/127 (18.1%) APL patients at an average of 11.5 days after the start of ATRA. All patients presented respiratory distress associated with increased ground-glass opacity in chest radiographies. Other accompanying symptoms were: fever not attributable to infection (65.2%), generalized edema (37.5%), weight gain (37.5%), and impairment of renal function (8.6%). We detected an association between development of DS and the AA genotype at Codon 469 of ICAM-1 (odds ratio of 3.5; 95% confidence interval: 1.2-10.2). Conversely, no significant association was detected between G241R or L125V polymorphisms at Exon 4 of ICAM-1 and Exon 3 of PECAM-1, respectively. Our results suggest that susceptibility to DS in APL patients may be influenced by genetic variation in adhesion molecule loci.

Celastrol Inhibits Lung Infiltration in Differential Syndrome Animal Models by Reducing TNF-α and ICAM-1 Levels while Preserving Differentiation in ATRA-Induced Acute Promyelocytic Leukemia Cells

“…Some researchers have highlighted the importance of ICAM-1 in building up excessive inflammation in DS. Dore et al reported that DS syndrome was related to some genotype with ICAM-1 [13], and Cunha De Santis et al found that ICAM-1 gene knockout abolished ATRA-caused inflammation-related syndrome in mice [14]. In light of this information and our own observations, we believe that ICAM-1 inhibition may be the major factor in celastrol’s action of preventing cell infiltration in lungs, though reductions in cytokines secretion may also contribute to this result.…”

“…Such expectancy is encouraged by our pre-experiment, which showed that celastrol could inhibit ATRA-caused ICAM-1 expression [12]. This is of importance considering that ICAM-1 plays a fundamental role in ATRA treatment-caused hyper-inflammation [13], [14].…”

“…Since ICAM-1 has been reportedly to be important for developing DS [13], [14], we further investigated at which level celastrol to exert its inhibitory effects on ICAM-1 expressions. In addition to inhibiting ICAM-1 surface levels, Western blot results showed that celastrol pre-loading for 30 min could dramatically inhibit whole cell (surface and intracellular) ICAM-1 elevation caused by 24 h ATRA induction (Figure 3b).…”

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

“…10,23,26,27,29 In addition, DS is often associated with the development of hyperleukocytosis, pulmonary edema, generalized edema, headache, and bone pain. 10,23,26,27,29,30 The diagnosis DS has proven to be difficult because none of the aforementioned symptoms is pathognomonic of the syndrome and can be the result of concurrent medical problems, such as bacteremia, sepsis, pneumonia, pulmonary hemorrhage, or congestive heart failure. 32,33 Therefore, DS may be underdiagnosed as well as overdiagnosed.…”

“…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 or maintenance therapy with ATRA and/or ATO in APL patients, nor is DS observed during ATRA treatment in non-APL malignancies, implicating that the APL cells play a crucial role in the development of DS. 6,7,14,20,23,26,27,31 DS is characterized by respiratory distress, unexplained fever, weight gain, interstitial pulmonary infiltrates, pleural or pericardial effusions, hypotension, and acute renal failure.…”