CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration

Abstract

Relapsed/refractory T cell acute lymphoblastic leukemia (T-ALL) is difficult to salvage especially in heavily pretreated patients, thus novel targeted agents are sorely needed.Hyperactivated JAK/STAT and BCL2 overexpression promote increased T-ALL proliferation and survival, and targeting these pathways with ruxolitinib and venetoclax may provide an alternative approach to achieve clinical remissions. Ruxolitinib and venetoclax show a dosedependent effect individually, but combination treatment synergistically reduces survival and proliferation of Jurkat and Loucy cells in vitro. Using a xenograft CXCR4+ Jurkat model, the combination treatment fails to improve survival, with death from hind limb paralysis. Despite ontarget inhibition by the drugs, histopathology demonstrates increased leukemic infiltration into the central nervous system (CNS), which expresses CXCL12, as compared to liver or bone marrow. Liquid chromatography-tandem mass spectroscopy shows that neither ruxolitinib nor venetoclax can effectively cross the blood-brain barrier, limiting efficacy against CNS T-ALL.Deletion of CXCR4 on Jurkat cells by CRISPR/Cas9 results in prolonged survival and a reduction in overall and neurologic clinical scores. While combination therapy with ruxolitinib and venetoclax shows promise for treating T-ALL, additional inhibition of the CXCR4-CXCL12 axis will be needed to eliminate both systemic and CNS T-ALL burden and maximize the possibility of complete remission.

Reviews on Biological Activity, Clinical Trial and Synthesis Progress of Small Molecules for the Treatment of COVID-19

“…It prevents the tyrosine phosphorylation of STAT1/3/5, which are downstream of cytokine receptors and drive T-ALL proliferation. Walker et al [ 159 ] proved that Ruxolitinib and venetoclax worked synergistically to treat T-ALL in vitro, but were not effective in vivo. CXCR4-CXCL12 was implicated as the potential pathway that drives T-ALL infiltration into the central nervous system (CNS).…”

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration

“…Unfortunately for most patients, chronic therapy with ruxolitinib results in reactivation of JAK/STAT signaling and prevents T-ALL remission. (17) In these cases, BCL2 may also be hijacked and upregulated to promote survival of these cancer cells. (1) Venetoclax is a highly potent and specific BH3 mimitec which binds to the BCL2 protein without targeting platelets.…”

“…Dosing of ruxolitinib or venetoclax alone decrease the survival and proliferation of T-ALL cells in vitroTo investigate the relevance of the JAK/STAT and BCL2 pathways on T-ALL proliferation and cell survival, Jurkat (mature T-ALL) and Loucy (early precursor T-ALL with high BCL2 expression) were assessed following treatment with either ruxolitinib or venetoclax (15,26). These cell lines were treated with a serial dose of ruxolitinib and venetoclax over the course of 72 h and evaluated using a trypan blue exclusion assay and MTT proliferation assay.Ruxolitinib and venetoclax were able to decrease the survival and proliferation of both Jurkat (Figure1B-E) and Loucy (Supplementary Figure 1) cell lines after 24, 48, and 72 h of treatment.…”