Abstract
Glucocorticoid (GC) resistance is a crucial determinant of inferior response to chemotherapy in pediatric acute lymphoblastic leukemia (ALL); however, molecular mechanisms underlying this phenomenon are poorly understood. Deregulated splicing is a common feature of many cancers, which impacts drug response and constitutes an attractive therapeutic target. Therefore, the aim of the current study was to characterize global splicing profiles associated with GC resistance and determine whether splicing modulation could serve as a novel therapeutic option for GC-resistant patients. To this end, 38 primary ALL samples were profiled using RNA-seq-based differential splicing analysis. The impact of splicing modulators was investigated in GC-resistant leukemia cell lines and primary leukemic specimens. Our findings revealed, for the first time, markedly distinct splicing landscapes in ALL samples of B-cell precursor (BCP)-ALL and T-ALL lineages. Differential splicing events associated with GC resistance were involved in RNA processing, a direct response to GCs, survival signaling, apoptosis, cell cycle regulation and energy metabolism. Furthermore, our analyses showed that GC-resistant ALL cell lines and primary samples are sensitive to splicing modulation, alone and in combination with GC. Together, these findings suggest that aberrant splicing is associated with GC resistance and splicing modulators deserve further interest as a novel treatment option for GC-resistant patients.
Highlights
Improvements achieved over the years in the treatment of childhood acute lymphoblastic leukemia (ALL) have resulted in five-year survival rates approaching or even exceeding 90% in some high-income countries [1,2]
In order to evaluate whether GC resistance is associated with specific splicing patterns in childhood ALL, we used RNA sequencing to profile transcriptomes of specimens obtained from 36 newly diagnosed and two relapsed pediatric ALL patients (Figure 1A)
We determined the immunophenotype and genetic profile of the samples, including mutations in glucocorticoid receptor (GR) and recurrent genetic alterations associated with ALL [21,38] (Figure 1C), which allowed us to account for possible confounders in the analysis
Summary
Improvements achieved over the years in the treatment of childhood acute lymphoblastic leukemia (ALL) have resulted in five-year survival rates approaching or even exceeding 90% in some high-income countries [1,2]. Up to 20% of patients experience a relapse which is largely caused by therapy resistance of leukemic cells and comes with a dismal prognosis. ALL patients are treated with combination chemotherapy, including glucocorticoids (GCs), in particular dexamethasone (Dex) and predniso(lo)ne (Pred), which are administered at induction the phase together with vincristine, L-asparaginase and anthracyclines [2,7,8]. In vitro resistance of primary childhood ALL cells to Pred was shown to correlate with both diminished short and long-term clinical response to chemotherapy [9,10]. Blasts isolated at relapse displayed higher GC resistance as compared to leukemic cells at diagnosis, which further underscores the importance of GCs in ALL treatment outcomes [11]
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