Abivertinib inhibits megakaryocyte differentiation and platelet biogenesis

doi:10.1007/s11684-021-0838-5

Front. Med.

2022, Vol. 16

Issue (3) : 416-428 https://doi.org/10.1007/s11684-021-0838-5

RESEARCH ARTICLE

Abivertinib inhibits megakaryocyte differentiation and platelet biogenesis

Jiansong Huang^1,²(

), Xin Huang^1,², Yang Li³, Xia Li^1,², Jinghan Wang^1,², Fenglin Li^1,², Xiao Yan⁴, Huanping Wang^1,², Yungui Wang^1,², Xiangjie Lin^1,², Jifang Tu^1,², Daqiang He⁵, Wenle Ye^1,², Min Yang^1,², Jie Jin^1,⁶(

)

¹. Department of Hematology, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
². Institute of Hematology, Zhejiang University School of Medicine, Hangzhou 310003, China
³. Department of Obstetrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
⁴. Department of Hematology, Qingdao Municipal Hospital, Qingdao 266000, China
⁵. Department of Laboratory Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
⁶. Cancer Center, Zhejiang University, Hangzhou 310058, China

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Abstract

Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton’s tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34⁺ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34⁺ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.

Keywords abivertinib Btk inhibitor platelet megakaryocyte megakaryopoiesis thrombopoiesis

Corresponding Author(s): Jiansong Huang,Jie Jin

Just Accepted Date: 19 August 2021 Online First Date: 18 November 2021 Issue Date: 18 July 2022

Cite this article:

Jiansong Huang,Xin Huang,Yang Li, et al. Abivertinib inhibits megakaryocyte differentiation and platelet biogenesis[J]. Front. Med., 2022, 16(3): 416-428.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0838-5
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I3/416

Fig.1 Effects of the abivertinib on the CFU-MK colony formation. (A) CFU-MK colonies formed from CD34⁺ HSCs treated with 0 (untreated, control), 2.5, and 5 mmol/L abivertinib for 12 days and measured using the CFU-MK assay kit. Representative macroscopic images of collagen slabs containing CFU-MK colonies (upper panels) and microscopic images of individual CFU-MK colonies formed by 0, 2.5, and 5 mmol/L abivertinib-treated cord blood CD34⁺ HSCs (lower panels) were obtained from three independent experiments. (B) Average numbers of small (5–10 MKs), intermediate (10–50 MKs), and large (>50 MKs) colonies per slide in three independent experiments. (C) Effect of increasing doses of abivertinib on the MK progenitor cell proliferation. Cell counts were measured by staining cells with Trypan blue. **P<0.01 (0 mmol/L abivertinib versus 5 mmol/L abivertinib). (D) CD34⁺ HSCs cultured in the presence of SCF/IL-3/IL-6/IL-9/TPO. Abivertinib or DMSO was then added to the medium on day 0. Apoptosis of the total cell population was analyzed using flow cytometry on day 6. Abivertinib slightly increased the apoptosis rate of CD34⁺ HSC-derived MK progenitor cells. (E) Statistical histograms showing the percentage of annexin V-positive apoptotic cells in panel D. Data were plotted as mean±SD ( n = 3). **P<0.01 compared with 0 mmol/L abivertinib. (F) Abivertinib-induced release of phosphatase from Meg-01 cells. Meg-01 cells were incubated with various concentrations of abivertinib at 37 °C for 30 min without stirring. The phosphatase activity was separately measured in the Meg-01 cell-free supernatant (■) and Meg-01 cell pellet (□) via enzyme-linked immunosorbent assay by using p-nitrophenyl phosphate as a chromogenic substrate. The Y-axis represents the optical density at 405 nm. Mean ± SD were obtained from three independent experiments. (G) Abivertinib-induced release of phosphatase from platelets. The Y-axis represents the optical density at 405 nm. (H) Release of hemoglobin from human erythrocytes induced by various concentrations of abivertinib. The extent of the release into the supernatant was measured at the absorbance at 405 nm. Triton X-100 and DMSO were used as positive and negative controls, respectively.

Fig.2 Effects of abivertinib on CD34⁺ HSC-derived MK differentiation, ploidy, and function. (A) Cord blood CD34⁺ HSCs induced to undergo MK differentiation in StemSpan SFEM II medium supplemented with SCF, IL-3, IL-6, IL-9, and TPO and cultured in the presence or absence of abivertinib. On day 12, the expression levels of CD61 and CD41a was analyzed using flow cytometry. Statistical histograms showed the mean fluorescence intensities (mean±SD) of CD41a and CD61 expression levels from three independent experiments. The units on the Y-axis are arbitrary. **P<0.01 (0 mmol/L abivertinib versus 5 mmol/L abivertinib). (B) Percentage of MKs in the total cell population, which was decreased by abivertinib in a dose-dependent manner. *P<0.05, **P<0.01 compared with 0 mmol/L abivertinib. (C) CD34⁺ HSC-derived MK ploidy (DNA content) analyzed using flow cytometry on day 12. CD41-positive cells were used to measure DNA ploidy. (D) Quantitative analysis of the percentage of cells with different levels of ploidy from three independent experiments. *P<0.05 and **P<0.01 (0 mmol/L abivertinib versus 5 mmol/L abivertinib). (E) Cord blood CD34⁺ HSC-derived MKs cultured in the presence or absence of abivertinib were allowed to adhere and spread on a fibrinogen-coated coverslip for two days. Nonadherent MKs were removed through PBS washing. Adherent and spreading MKs were labeled with TRITC–phalloidin (red) and CD41a antibody (FITC, green). Nuclei were stained with DAPI (blue). Quantitative determinations of cell numbers, the area of the spreading cells, and the size of the nuclei are shown in Fig. 3A–3C. Merged and brightfield images are shown in Fig. S3. The scale bar is 80 mm.

Fig.3 Effects of abivertinib on CD34⁺ HSC-derived MK adhesion, spreading, and proplatelet formation. (A) Statistical histograms showing the cell numbers per field. The numbers of cells were decreased by abivertinib in a dose-dependent manner. *P<0.05, **P<0.01 compared with control (0 mmol/L abivertinib). (B) Statistical histograms showing the pixel area of the spreading of cells cultured in the presence or absence of abivertinib. The spreading of cells was inhibited by abivertinib in a dose-dependent manner. *P<0.05, **P<0.01 compared with control (0 mmol/L abivertinib). (C) CD34⁺ HSC-derived MKs treated with increasing doses of abivertinib showing decreased nuclear area. *P<0.05 (0 mmol/L abivertinib versus 2.5 mmol/L abivertinib), and **P<0.01 (0 mmol/L abivertinib versus 5 mmol/L abivertinib). The units on the Y-axis are arbitrary. (D) Images of CD34⁺ HSC-derived MKs under an inverted microscope taken on day 12. The data shown are representative pictures of MKs from one of three experiments with similar results. Proplatelet-bearing MKs are indicated by black arrows. The scale bar is 60 mm. Abivertinib has a strong ability to inhibit proplatelet formation. (E) Histograms representing the number of proplatelet-bearing MKs per 10³ MKs. **P<0.01.

Fig.4 Effects of abivertinib on Meg-01-derived MK differentiation. (A) Meg-01 cells treated with 10 nmol/L PMA to induce differentiation and cultured in the presence or absence of abivertinib (1.25, 2.5, 5, 10, and 20 mmol/L) for four days. All figures show representative images of the morphologic features of Meg-01 cells on day 2. The scale bar is 60 mm. (B) Representative images of the morphologic features of Meg-01 cells on day 4. Panels A and B show that Meg-01 cells decreased in size and exhibited fewer cytoplasmic extensions with increasing abivertinib concentrations compared with the control. Concurrently, the numbers of Meg-01 cells decreased with increasing abivertinib concentrations. (C) Quantification of the pixel areas (arbitrary) of the spreading Meg-01 cells on day 4 (panel B). (D) qRT-PCR analysis of CD61 mRNA levels in PMA-induced Meg-01 cells cultured in the presence or absence of abivertinib. Data are shown as mean±SD (n = 3). (E) qRT-PCR analysis of CD41a mRNA levels in PMA-induced Meg-01 cells cultured in the presence or absence of abivertinib. Data are shown as mean±SD (n = 3).

Fig.5 Effects of abivertinib on MK and platelet counts in mice. (A) C57BL/6 mice treated with CMC (control) or low (80 mg/kg/day), medium (160 mg/kg/day), or high (320 mg/kg/day) dosages of abivertinib for 11 consecutive days. Platelet counts were measured on days -1 (before treatment), 1, 4, 7, and 11. **P<0.01 between the high-dose abivertinib and CMC groups. n = 6 mice per group. (B) Plasma TPO levels in abivertinib-treated mice. Plasma TPO levels did not change with abivertinib treatment. (C) Representative H&E sections of murine femurs from mice treated with CMC (control) or low (80 mg/kg/day), medium (160 mg/kg/day), or high (320 mg/kg/day) dosages of abivertinib for 11 days (scale bar= 50 mm). MKs are indicated by white arrows. (D) Quantification of the number of MKs in the BM from CMC- and abivertinib-treated mice. (E) Representative longitudinal sections of H&E-stained spleens from mice treated with CMC (control) or low (80 mg/kg/day), medium (160 mg/kg/day), or high (320 mg/kg/day) dosages of abivertinib for 11 days. MKs are indicated by white arrows. The scale bar is 50 mm. (F) Quantification of the number of MKs in spleens from CMC- and abivertinib-treated mice. ns, not significant.

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[8]	GONG Xiaowei, WEI Jie, LI Yusheng, CHENG Weiwei, DENG Peng, JIANG Yong. Involvement of p38 mitogen-activated protein kinase in the regulation of platelet-derived growth factor -induced cell migration[J]. Front. Med., 2007, 1(3): 248-252.

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