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Research in the last few years has revealed that leukaemic cells can remodel the bone marrow niche into a permissive environment favouring leukaemic stem cell expansion. Tumour‐associated macrophages (TAMs) are prominent components of the tumour microenvironment and play an important role in the onset and progression of solid tumours. However, little is known about their role in the development of acute lymphoblastic leukaemia (ALL). Using a unique mouse model of T‐ALL induced by injection of EL4 T‐cell lymphoma cells to syngeneic C57BL/6 mice, we report herein that ALL leads to the invasion of leukaemia‐associated monocyte‐derived cells (LAMs) into the bone marrow and spleen of T‐ALL mice. Furthermore, we found that leukaemia cells could polarize bone marrow–derived macrophages (BMDMs) into LAMs. In turn, LAMs were able to protect leukaemia cells from drug‐induced apoptosis in vitro. Therapies targeted against the TAMs by inhibiting colony stimulating factor‐1 receptor (CSF‐1R) have emerged as a promising approach for cancer treatment. In this study, we demonstrate that CSF‐1R inhibition inhibits the viability of BMDMs, blocks LAMs polarization and reduces the abundance of LAMs in T‐ALL mice. In vivo, combination treatment of CSF‐1R inhibitor and vincristine (VCR) dramatically increased the survival of T‐ALL mice and delayed leukaemia progression compared with VCR monotherapy. Finally, these data reinforce the role of microenvironments in leukaemia and suggest that macrophages are a potential target for the development of novel therapeutic strategies in T‐ALL.

Imatinib mesylate (IM) is the first-line treatment for Philadelphia (Ph) chromosomal positive leukemia by inhibiting phosphorylation of substrates via binding to the ABL kinase domain. Because of the drug resistance, side effects and the high cost of IM, it is necessary to find anti-cancer drugs with relatively low toxicity and cost, and enhanced efficacy, such as traditional Chinese medicines (TCMs). As one of TCMs, Huai Qi Huang (HQH) was chosen to treat BV173 and K562 cells. Various concentrations of HQH were added to cells for 24–72 h. Co-treatment of HQH and trametinib, an MEK inhibitor, was used to verify the synergistic effects on cell viability and apoptosis. Knockdown and overexpression of mitogen-activated protein kinase kinase 4 (MEK4) were implemented to demonstrate the role of MEK in cell apoptosis. Cell viability and apoptosis were measured by cell counting kit-8 assay (CCK8) and flow cytometry, respectively. Western blotting and real-time quantitative PCR (RT-qPCR) were used to assess protein and mRNA expression levels, respectively. The results showed that HQH inhibited survival and promoted apoptosis of BV173 and K562 cells in a dose-dependent manner, accompanied with down-regulation of PRKCH mRNA as well as CRAF, MEK4, phospho-ERK (pERK) and BCL2 proteins, and up-regulation of cleaved caspase3 protein. Co-treatment of HQH and trametinib had a synergistic effect on inhibiting survival and promoting apoptosis. MEK4 knockdown increased apoptosis, and had a synergistic effect with HQH. In contrast, MEK4 overexpression decreased apoptosis, and had the opposite effect with HQH. Collectively, the results of this study may identify a therapeutic mechanism of HQH on promoting apoptosis, and provide a potential option for treatment of Ph+ leukemia.

Imatinib mesylate (IM) is the first-line treatment for Philadelphia (Ph) chromosomal positive leukemia by inhibiting phosphorylation of substrates via binding to the ABL kinase domain. Because of the drug resistance, side effects and the high cost of IM, it is necessary to find anti-cancer drugs with relatively low toxicity and cost, and enhanced efficacy, such as traditional Chinese medicines (TCMs). As one of TCMs, Huai Qi Huang (HQH) was chosen to treat BV173 and K562 cells. Various concentrations of HQH were added to cells for 24-72 h. Co-treatment of HQH and trametinib, an MEK inhibitor, was used to verify the synergistic effects on cell viability and apoptosis. Knockdown and overexpression of mitogen-activated protein kinase kinase 4 (MEK4) were implemented to demonstrate the role of MEK in cell apoptosis. Cell viability and apoptosis were measured by cell counting kit-8 assay (CCK8) and flow cytometry, respectively. Western blotting and real-time quantitative PCR (RT-qPCR) were used to assess protein and mRNA expression levels, respectively. The results showed that HQH inhibited survival and promoted apoptosis of BV173 and K562 cells in a dose-dependent manner, accompanied with down-regulation of PRKCH mRNA as well as CRAF, MEK4, phospho-ERK (pERK) and BCL2 proteins, and up-regulation of cleaved caspase3 protein. Co-treatment of HQH and trametinib had a synergistic effect on inhibiting survival and promoting apoptosis. MEK4 knockdown increased apoptosis, and had a synergistic effect with HQH. In contrast, MEK4 overexpression decreased apoptosis, and had the opposite effect with HQH. Collectively, the results of this study may identify a therapeutic mechanism of HQH on promoting apoptosis, and provide a potential option for treatment of Ph