Circulating lnc-LOC as a novel noninvasive biomarker in the treatment surveillance of acute promyelocytic leukaemia

Abstract

Background: Acute promyelocytic leukaemia (APL) is a unique subtype of acute myeloid leukaemia (AML) characterized by haematopoietic failure caused by the accumulation of abnormal promyelocytic cells in bone marrow (BM). However, indispensable BM biopsy frequently afflicts patients in leukaemia surveillance, which increases the burden on patients and reduces compliance. This study aimed to explore whether the novel circulating long noncoding RNA LOC100506453 (lnc-LOC) could be a target in diagnosis, assess the treatment response and supervise the minimal residual disease (MRD) of APL, thereby blazing a trail in noninvasive lncRNA biomarkers of APL.

Methods: Our study comprised 100 patients (40 with APL and 60 with non-APL AML) and 60 healthy donors. BM and peripheral blood (PB) sample collection was accomplished from APL patients at diagnosis and postinduction. Quantitative real-time PCR (qRT-PCR) was conducted to evaluate lnc-LOC expression. A receiver operating characteristic (ROC) analysis was implemented to analyse the value of lnc-LOC in the diagnosis of APL and treatment monitoring. For statistical analysis, the Mann-Whitney U test, a t test, and Spearman's rank correlation test were utilized.

Results: Our results showed that BM lnc-LOC expression was significantly different between APL and healthy donors and non-APL AML. lnc-LOC was drastically downregulated in APL patients' BM after undergoing induction therapy. Lnc-LOC was upregulated in APL cell lines and downregulated after all-trans retinoic acid (ATRA)-induced myeloid differentiation, preliminarily verifying that lnc-LOC has the potential to be considered a treatment monitoring biomarker. PB lnc-LOC was positively correlated with BM lnc-LOC in APL patients, non-APL AML patients and healthy donors and decreased sharply after complete remission (CR). However, upregulated lnc-LOC was manifested in relapsed-refractory patients. A positive correlation was revealed between PB lnc-LOC and PML-RARα transcript levels in BM samples. Furthermore, we observed a positive correlation between PB lnc-LOC and BM lnc-LOC expression in APL patients, suggesting that lnc-LOC can be utilized as a noninvasive biomarker for MRD surveillance.

Conclusions: Our study demonstrated that PB lnc-LOC might serve as a novel noninvasive biomarker in the treatment surveillance of APL, and it innovated the investigation and application of newly found lncRNAs in APL noninvasive biomarkers used in diagnosis and detection.

Keywords: Acute promyelocytic leukaemia; Lnc-LOC; Minimal residual disease; Noninvasive biomarker; Surveillance.

Fig. 1

BM lnc-LOC expression and diagnostic value in APL patients. a Comparison of BM lnc-LOC expression in different groups, including APL, non-APL AML and healthy donors. b ROC curve analysis of BM lnc-LOC expression for the discrimination of APL from healthy donors. c ROC curve analysis of lnc-LOC expression for the discrimination of APL from non-APL AML. d ROC curve analysis of lnc-LOC expression for the discrimination of non-APL AML from healthy donors. * Statistically significant

Fig. 2

Differential expression of lnc-LOC in myeloid lineage and ATRA-treated APL cells. a lnc-LOC expression in myeloid lineage cells, including NB4, HL-60, U937, THP-1, K562, Kasumi-6, and HEL cells. b lnc-LOC expression in HL-60 cells treated with ATRA as indicated. c lnc-LOC expression in NB4 cells treated with ATRA as indicated. d PML-RARα transcript expression in NB4 cells treated with ATRA as indicated. e lnc-LOC expression in NB4 cells was positively correlated with PML-RARα transcript expression after ATRA treatment in NB4 cells. * Statistically significant

Fig. 3

Correlation between lnc-LOC expression in PB samples and that in BM samples from APL patients. a Comparison of PB lnc-LOC expression in APL, non-APL AML and healthy donors. b PB lnc-LOC expression was positively correlated with BM lnc-LOC expression in APL at diagnosis (R² = 0.936, P < 0.001*). c PB lnc-LOC expression was positively correlated with BM lnc-LOC expression in non-APL AML (R² = 0.918, P < 0.001*). d PB lnc-LOC expression was positively correlated with BM lnc-LOC expression in healthy donors (R² = 0.910, P < 0.001*). e A significant positive correlation was observed between all PB samples and BM samples in lnc-LOC expression (R² = 0.963, P < 0.001*). * Statistically significant

Fig. 4

Utilization of PB lnc-LOC in monitoring the treatment response of APL patients. a PB lnc-LOC expression in 40 APL patients at new diagnosis, postinduction and CR. b PB lnc-LOC expression in 5 representative relapsed APL patients at different periods (at diagnosis, CR and relapse). * Statistically significant

Fig. 5

PB lnc-LOC as a potential MRD monitoring marker for APL patients. a PB lnc-LOC levels were positively correlated with PML-RARα transcript expression in APL patients at diagnosis (R² = 0.949, P < 0.001*). b PB lnc-LOC levels were positively correlated with PML-RARα transcript expression in APL patients postinduction (R² = 0.934, P < 0.001*). c PB lnc-LOC levels were consistently correlated with MRD values in APL patients postinduction (R² = 0.904, P < 0.001*). * Statistically significant