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A. Gao et al.
and in megakaryoblastic cell lines.47 This suggests that the NF-E2 transcription factor might participate in the molec- ular mechanism of IL-4-induced defective MK differenti- ation and polyploidization in AML, but this requires fur- ther investigation.
Despite the marked response of LKS+ cells to in vitro IL- 4 stimulation, IL-4 appeared to act to a greater degree on the last step of MK differentiation, rather than on LT- HSC. Studies showed that MK could originate directly from an upstream HSC subpopulation, independently of other lineage fates.21,22 Therefore, the increase of vWF+ LT- HSC in IL-4-treated mice was more likely to be a com- pensation for MK reduction. In our AML mouse model, the number of PreMegE was dramatically reduced, while the decrease of MkP was less marked, which suggests that HSC compensated for the deficiency of MkP through the non-canonical route. In addition, the increase of vWF+ LT-HSC in IL-4-treated mice was consistent with the phe- nomenon observed in MK-depleted mouse models,48 sug- gesting the role of vWF+ LT-HSC as MK reserves in native hematopoiesis and their relative resistance to stimuli. Thus, the blocked differentiation of LT-HSC in AML BM appears to result from a complex of factors, rather than IL-4 alone, including signals from niche cells, which require intensive research since they cannot be corrected easily by conventional cytotoxic therapy.
Studies have shown that leukemic cells impair the func- tion of normal hematopoiesis by causing a significant change in a variety of niche cells and secreting cytokines in the BM microenvironment.3,6-9 In our study, the admin- istration of IL-4 inhibitors alone to leukemic mice did not increase platelet counts in the peripheral blood, likely due to the absence of a specific effect of IL-4 inhibitors on leukemic cells. Currently the standard treatment of leukemia is primarily chemotherapy.43 It has been reported
that AML patients given induction treatment with high- dose cytarabine had a considerably longer period of thrombocytopenia and received significantly more platelet transfusions in comparison to patients in the inter- mediate-dose group.49 Thus, it is important to use hematopoietic growth factors to accelerate platelet recov- ery. In our study, anti-IL-4 was administered in combina- tion with chemotherapy, with results suggesting that this has clinical potential for alleviating thrombocytopenia in AML. Additionally, anti-IL-4 has been shown to be safe when administered to patients with asthma,50 implying that it could be applied in the treatment of AML. In our current study, all the data were generated based on a spe- cific AML model and it is unclear whether results obtained can be generalized to other types of AML. More studies are, therefore, needed to expand this paradigm to other types of leukemia and to explore whether our findings in the mouse model can be translated to human AML.
In summary, our present study systemically describes defective megakaryopoiesis from HSC in AML and for the first time identifies BM endothelial cell-derived IL-4 as a candidate factor responsible for thrombocytopenia and a potential therapeutic target, in conjunction with chemotherapy, in patients with AML.
Acknowlegments
We thank Rong Guo (Cnkingbio Company) for technical sup- port. This work was supported by grants from the National Key Research and Development Program of China (2016YFA0100600, 2017YFA0103400); the National Natural Science Foundation of China (81421002, 81730006, 81430004, 81670106, 81870086, 8181101081); CAMS Initiative for Innovative Medicine (2017-I2M-3-009, 2016-I2M-1-017); and the CAMS Fundamental Research Funds for Central Research Institutes (2016GH3100001, 2018PT31005).
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