Mer receptor tyrosine kinase is a therapeutic target in pre–B-cell acute lymphoblastic leukemia

Abstract

• Mer tyrosine kinase is aberrantly expressed in ;30% of pediatric pre-B-ALL patients, including most patients with an E2A-PBX1 translocation.• Mer inhibition decreased B-ALL cell survival signal transduction, caused chemosensitization, and prolonged survival in a xenograft model.Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 85%. However, alterations to treatment strategies using available drugs are unlikely to provide significant improvement in survival or decrease therapy-associated toxicities. Here, we report ectopic expression of the Mer receptor tyrosine kinase in pre-B-cell ALL (B-ALL) cell lines and pediatric patient samples. Inhibition of Mer in B-ALL cell lines decreased activation of AKT and MAPKs and led to transcriptional changes, including decreased expression of antiapoptotic PRKCB gene and increase in proapoptotic BAX and BBC3 genes. Further, Mer inhibition promoted chemosensitization, decreased colony-forming potential in clonogenic assays, and delayed disease onset in a mouse xenograft model of leukemia. Our results identify Mer as a potential therapeutic target in B-ALL and suggest that inhibitors of Mer may potentiate lymphoblast killing when used in combination with chemotherapy. This strategy could reduce minimal residual disease and/or allow for chemotherapy dose reduction, thereby leading to improved event-free survival and reduced therapy-associated toxicity for patients with B-ALL. Additionally, Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications. (Blood. 2013;122(9):1599-1609

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

“…12 Our data provide evidence that Mer leads to the survival of t(1;19) ALL cells in cocultures mimicking the CNS. The upregulation of total Mer in coculture may be due to feedback mechanisms inducing Mer as a compensation for low or absent Gas6, or, by Mer activation through Galectin-3, potentially in conjunction with apoptotic cells.…”

“…on May 9, 2018. by guest www.bloodjournal.org From recapitulating data in smaller cohorts 12,27 (supplemental Figure 4). Interestingly, none of the t(1;19)-negative patient groups showed Mer mRNA levels similar to the t(1;19) patients, no matter if they were BCP-or T-lineage ALLs and regardless of signs of CNS infiltration at initial diagnosis or if patients suffered from CNS relapse ( Figure 6B).…”

“…Gas6, a major activator of Mer signaling, is usually secreted in the bone marrow and considered a pro-proliferative signal. 1,12 In contrast to MSC cells, U343 cells did not secrete Gas6 ( Figure 3A). No paracrine effects between ALL and U343 cells potentiating Gas6 secretion 1 could be observed as supernatants of U343 cocultures contained low or no Gas6 (supplemental Figure 2A).…”

“…10 Studies overexpressing Mer in fibroblasts found that it can induce extracellular signalregulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, nuclear factor-kB (NF-kB) and enhance cell survival via phosphatidylinositol 3-kinase (PI3K)/AKT. 2,11 Linger et al 12 reported that Mer is overexpressed on pre-B-cell ALL (B-ALL) cells of pediatric patients with t(1;19)(q23;p13) translocation. Furthermore, inhibition of Mer by RNA interference (RNAi) reduced survival and chemoresistance of pre-B-ALL cell lines and prolonged survival of xenografts.…”

“…Furthermore, inhibition of Mer by RNA interference (RNAi) reduced survival and chemoresistance of pre-B-ALL cell lines and prolonged survival of xenografts. 12 Pediatric ALL with t(1;19)(q23;p13) translocation is found in about 3% to 5% of ALL patients and has an overall favorable prognosis. 13 However, this translocation has been associated with late development of secondary malignancies such as mixed lineage leukemia (MLL)-rearranged AML and myelodysplastic syndrome.…”