RUNX1 transactivates BCR‐ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia

Abstract

The emergence of tyrosine kinase inhibitors as part of a front‐line treatment has greatly improved the clinical outcome of the patients with Ph+ acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR‐ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)‐resistant Ph+ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR‐ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb‐M'. Through a series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR‐ABL1 expression in Ph+ ALL cell lines. These cells showed significantly reduced expression of BCR‐ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb‐M' consistently downregulated the expression of BCR‐ABL1 in these cells and this drug was highly effective even in an imatinib‐resistant Ph+ ALL cell line. In good agreement with these findings, forced expression of BCR‐ABL1 in these cells conferred relative resistance to Chb‐M'. In addition, in vivo experiments with the Ph+ ALL patient‐derived xenograft cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph+ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR‐ABL1. Chb‐M' could be a novel drug for patients with TKI‐resistant refractory Ph+ ALL.

The first Japanese biobank of patient‐derived pediatric acute lymphoblastic leukemia xenograft models

“…Therefore, we compared the clonal architecture in a PDX model and its dynamics with that in the patient from which the cells were derived. A 6‐year‐old girl, diagnosed with Philadelphia chromosome‐positive ALL, suffered a secondary disease relapse during maintenance therapy with dasatinib after hematopoietic transplantation 29 . Leukemic cells at diagnosis and at secondary relapse were analyzed by FISH to detect the BCR‐ABL fusion.…”

“…A 6‐year‐old girl, diagnosed with Philadelphia chromosome‐positive ALL, suffered a secondary disease relapse during maintenance therapy with dasatinib after hematopoietic transplantation. 29 Leukemic cells at diagnosis and at secondary relapse were analyzed by FISH to detect the BCR‐ABL fusion. At diagnosis, a major subpopulation (740/1000 cells) showed triple fusion signals, whereas at secondary relapse 900/1000 cells showed quadruple fusion signals (Figure 5A ).…”

“…A 6-year-old girl, diagnosed with Philadelphia chromosome-positive ALL, suffered a secondary disease relapse during maintenance therapy with dasatinib after hematopoietic transplantation. 29 One of the advantages of our PDX biobank is that most of the primary samples were derived from patients with relapsed and refractory ALL. PDX models of patients with relapsed and refractory pediatric ALL are in high demand because prognosis remains poor for such patients.…”

Circular RNA CircSLC8A1 contributes to osteogenic differentiation in hBMSCs via CircSLC8A1/miR‐144‐3p/RUNX1 in periprosthetic osteolysis

“… 26 RUNX1 is involved in embryogenesis, leukaemia, vascularization, immune response and tumour formation. 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 But more importantly, RUNX1 has been also reported to assume an essential function in bone homeostasis. According to the research of osteoporosis in male including 822 volunteers aged 65 years or older, results pointed out that RUNX1 was a potential genetic regulatory of bone formation by measuring cortical bone and cancellous density in humans.…”

“…Runt‐related transcription factor 1 (RUNX1), a member of the RUNX family, is one of the key regulatory proteins in vertebrates 26 . RUNX1 is involved in embryogenesis, leukaemia, vascularization, immune response and tumour formation 27–35 . But more importantly, RUNX1 has been also reported to assume an essential function in bone homeostasis.…”