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Cited by 5Acute Myeloid Leukemia ResearchChronic Myeloid Leukemia TreatmentsLung Cancer Treatments and Mutations

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Osimertinib Covalently Binds to CD34 and Eliminates Myeloid Leukemia Stem/Progenitor Cells

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Xia, Li, Liu, Jie-Yang, Yang, Meng-Ying, Zhang, Xue-Hong, Jiang, Yue, Yin, Qian-Qian, Luo, Chen-Hui, Liu, Hong-Chen, Kang, Zhi-Jie, Zhang, Cheng-Tao, Gao, Bei-Bei, Zhou, Ai-Wu, Cai, Hai-Yan, Waller, Edmund K., Yan, Jin-Song, Lu, Ying·2024·Cancer Research
DOI 10.1158/0008-5472.can-23-1632PMC PMC10831336

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Abstract

Osimertinib is a third-generation covalent EGFR inhibitor that is used in treating non–small cell lung cancer. First-generation EGFR inhibitors were found to elicit pro-differentiation effect on acute myeloid leukemia (AML) cells in preclinical studies, but clinical trials yielded mostly negative results. Here, we report that osimertinib selectively induced apoptosis of CD34+ leukemia stem/progenitor cells but not CD34− cells in EGFR-negative AML and chronic myeloid leukemia (CML). Covalent binding of osimertinib to CD34 at cysteines 199 and 177 and suppression of Src family kinases (SFK) and downstream STAT3 activation contributed to osimertinib-induced cell death. SFK and STAT3 inhibition induced synthetic lethality with osimertinib in primary CD34+ cells. CD34 expression was elevated in AML cells compared with their normal counterparts. Genomic, transcriptomic, and proteomic profiling identified mutation and gene expression signatures of patients with AML with high CD34 expression, and univariate and multivariate analyses indicated the adverse prognostic significance of high expression of CD34. Osimertinib treatment induced responses in AML patient-derived xenograft models that correlated with CD34 expression while sparing normal CD34+ cells. Clinical responses were observed in two patients with CD34high AML who were treated with osimertinib on a compassionate-use basis. These findings reveal the therapeutic potential of osimertinib for treating CD34high AML and CML and describe an EGFR-independent mechanism of osimertinib-induced cell death in myeloid leukemia. Significance: Osimertinib binds CD34 and selectively kills CD34+ leukemia cells to induce remission in preclinical models and patients with AML with a high percentage of CD34+ blasts, providing therapeutic options for myeloid leukemia patients.

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Figure 1. EGFR inhibitors induce apoptosis of CD34+ leukemia cells. A, CD34+ cells purified from BMMC of patients with AML were treated with indicated concentrations of osimertinib for 72 hours. Cell apoptosis was measured by Annexin V/PI staining. Representative flow cytometry plots of CD34+ cells from three AML individuals are shown. Bottom, cell viability measured by trypan blue (n = 10 patient samples; left) and quantified Annexin V+PI− and Annexin V+PI+ cells (n = 10 patient samples; right). B, CD34+ cells purified from BMMCs of patients with AML were treated with indicated concentrations of osimertinib for 72 hours. Cell apoptosis was quantified by Annexin V/PI staining. Flow cytometry plots are shown. Bottom, cell viability measured by trypan blue and quantified Annexin V+PI− and Annexin V+PI+ cells (n = 8). C, KG-1 and Kasumi-1 were treated with 2 μmol/L osimertinib, erlotinib, or ibrutinib for 72 hours. Representative flow cytometry plots and quantified Annexin V+PI− and Annexin V+PI+ cells are shown. D, Primary CML CD34+ cells were treated with 1 μmol/L osimertinib for 72 hours. Representative flow cytometry plots, cell viability measured by trypan blue, and quantified Annexin V+PI− and Annexin V+PI+ cells are shown. **, P < 0.005; ***, P < 0.001; ****, P < 0.0001, against control (ctrl) group. E, CD34+CD38− cells purified from patients with AML (n = 3) were treated with 2 μmol/L osimertinib, 2 μmol/L daunorubicin or osimertinib plus daunorubicin (combo), and cell apoptosis was measured by Annexin V staining. *, P < 0.05; **, P < 0.001, between the line-pointed group. F, KG-1 and Kasumi-1 cells were treated with osimertinib and the indicated proteins were detected by Western blot. G, KG-1 cells were treated with osimertinib, necrostatin-1, or osimertinib plus necrostatin-1, and cell apoptosis was measured by Annexin V/PI staining. *, P < 0.05, between the line-pointed group; NS, not significant.
Figure 1. EGFR inhibitors induce apoptosis of CD34+ leukemia cells. A, CD34+ cells purified from BMMC of patients with AML were treated with indicated concentrations of osimertinib for 72 hours. Cell apoptosis was measured by Annexin V/PI staining. Representative flow cytometry plots of CD34+ cells from three AML individuals are shown. Bottom, cell viability measured by trypan blue (n = 10 patient samples; left) and quantified Annexin V+PI− and Annexin V+PI+ cells (n = 10 patient samples; right). B, CD34+ cells purified from BMMCs of patients with AML were treated with indicated concentrations of osimertinib for 72 hours. Cell apoptosis was quantified by Annexin V/PI staining. Flow cytometry plots are shown. Bottom, cell viability measured by trypan blue and quantified Annexin V+PI− and Annexin V+PI+ cells (n = 8). C, KG-1 and Kasumi-1 were treated with 2 μmol/L osimertinib, erlotinib, or ibrutinib for 72 hours. Representative flow cytometry plots and quantified Annexin V+PI− and Annexin V+PI+ cells are shown. D, Primary CML CD34+ cells were treated with 1 μmol/L osimertinib for 72 hours. Representative flow cytometry plots, cell viability measured by trypan blue, and quantified Annexin V+PI− and Annexin V+PI+ cells are shown. **, P < 0.005; ***, P < 0.001; ****, P < 0.0001, against control (ctrl) group. E, CD34+CD38− cells purified from patients with AML (n = 3) were treated with 2 μmol/L osimertinib, 2 μmol/L daunorubicin or osimertinib plus daunorubicin (combo), and cell apoptosis was measured by Annexin V staining. *, P < 0.05; **, P < 0.001, between the line-pointed group. F, KG-1 and Kasumi-1 cells were treated with osimertinib and the indicated proteins were detected by Western blot. G, KG-1 cells were treated with osimertinib, necrostatin-1, or osimertinib plus necrostatin-1, and cell apoptosis was measured by Annexin V/PI staining. *, P < 0.05, between the line-pointed group; NS, not significant.CC BY-NC-ND · PubMed Central
Figure 2. Osimertinib selectively kills CD34+ AML and CML cells. A, Primary CD34− cells were treated with 2 μmol/L osimertinib for 72 hours. Cell apoptosis was measured by Annexin V/PI staining. Representative flow cytometry plots, cell viability measured by trypan blue, and quantification of Annexin V+% are shown. B, BMMCs of patients with AML (n = 17) were treated with 2 μmol/L osimertinib for 48 hours and cell apoptosis was measured by Annexin V/PI assay co-staining with CD34-APC. Flow cytometry plots of two representative patients and quantification of Annexin V+% are shown. C, Leukemia cell lines KG-1, Kasumi-1, U937, THP1, Molm13, and K562 were treated with 2 μmol/L osimertinib for 72 hours and Annexin V+% was measured by Annexin V/PI assay co-staining with CD34-APC. Right, quantification of Annexin V+PI− and Annexin V+PI+ cells. *, P < 0.01; ****, P < 0.0001, between the line-pointed group.
Figure 2. Osimertinib selectively kills CD34+ AML and CML cells. A, Primary CD34− cells were treated with 2 μmol/L osimertinib for 72 hours. Cell apoptosis was measured by Annexin V/PI staining. Representative flow cytometry plots, cell viability measured by trypan blue, and quantification of Annexin V+% are shown. B, BMMCs of patients with AML (n = 17) were treated with 2 μmol/L osimertinib for 48 hours and cell apoptosis was measured by Annexin V/PI assay co-staining with CD34-APC. Flow cytometry plots of two representative patients and quantification of Annexin V+% are shown. C, Leukemia cell lines KG-1, Kasumi-1, U937, THP1, Molm13, and K562 were treated with 2 μmol/L osimertinib for 72 hours and Annexin V+% was measured by Annexin V/PI assay co-staining with CD34-APC. Right, quantification of Annexin V+PI− and Annexin V+PI+ cells. *, P < 0.01; ****, P < 0.0001, between the line-pointed group.CC BY-NC-ND · PubMed Central
Figure 3. Osimertinib downregulates level of tyrosine phosphorylation of CD34. A, Heat map of levels of the indicated phosphorylated tyrosine sites in osimertinib-treated and untreated (ctrl) CD34+ cells. The CD34+ cells were purified from three AML individuals and pooled, followed by treatment with 2 μmol/L osimertinib for 48 hours. Tyrosine-phosphorylated peptides were enriched and analyzed by MS. The colors in the map represent the quantitative value (normalized total spectra) according to the Scaffold_4.3.3. B, Phosphoproteome changes observed in osimertinib-treated CD34+ cells analyzed by String database. The edge indicates known interaction between two proteins. Sequence logo represents the motif clustering from the tyrosine phosphorylation data set. C and D, The osimertinib treated or untreated CD34+ cells were collected and the cell lysates were immunoprecipitated with anti-CD34 or IgG antibodies, followed by PRM-MS analysis. Intensity histogram of nonphosphorylated (C) and phosphorylated Y329-containing peptide (D) of CD34 protein was quantified. E, Level of Y329-phosphorylation of CD34 quantified by PRM-MS assays in AML cell lines and 5 primary AML CD34+ samples. Data are representative of three independent experiments. *, P < 0.05; **, P < 0.01, against untreated group.
Figure 3. Osimertinib downregulates level of tyrosine phosphorylation of CD34. A, Heat map of levels of the indicated phosphorylated tyrosine sites in osimertinib-treated and untreated (ctrl) CD34+ cells. The CD34+ cells were purified from three AML individuals and pooled, followed by treatment with 2 μmol/L osimertinib for 48 hours. Tyrosine-phosphorylated peptides were enriched and analyzed by MS. The colors in the map represent the quantitative value (normalized total spectra) according to the Scaffold_4.3.3. B, Phosphoproteome changes observed in osimertinib-treated CD34+ cells analyzed by String database. The edge indicates known interaction between two proteins. Sequence logo represents the motif clustering from the tyrosine phosphorylation data set. C and D, The osimertinib treated or untreated CD34+ cells were collected and the cell lysates were immunoprecipitated with anti-CD34 or IgG antibodies, followed by PRM-MS analysis. Intensity histogram of nonphosphorylated (C) and phosphorylated Y329-containing peptide (D) of CD34 protein was quantified. E, Level of Y329-phosphorylation of CD34 quantified by PRM-MS assays in AML cell lines and 5 primary AML CD34+ samples. Data are representative of three independent experiments. *, P < 0.05; **, P < 0.01, against untreated group.CC BY-NC-ND · PubMed Central
Figure 4. Osimertinib directly binds to CD34 protein. A, Chemical structure of biotin-tagged osimertinib. B, Pulldown assays were conducted using biotin-osimertinib against recombinant CD34 (rCD34) in the presence/absence of free osimertinib as a competitor. C, Pulldown assays were conducted using biotin-osimertinib against KG-1 cell lysates in the presence/absence of free osimertinib as a competitor. D, MS/MS analysis of the cysteine 199 (C199) tryptic peptide of rCD34 protein incubated with (bottom) or without (top) osimertinib for 30 minutes. E, Predicted conformations of compound osimertinib (magenta) and ibrutinib (cyan) in the binding pocket of CD34. The protein of CD34 is shown in wheat surface and cartoon. Compounds are shown as sticks. Cys177 and Cys199 of CD34 are shown as sticks. The dark dash lines show the distance between Cys199/Cys177 to the atom that is involved in Michael addition (in dash cycles). F, KG-1, Kasumi-1, and primary AML cells were infected with CD34-targeting CRISPR-Cas9 to deplete CD34 expression. Expression of CD34 was analyzed with immunoblot assay. G, CD34 was knocked out by CRISPR-Cas9 system in CD34+ cells purified from patients with AML (n = 3) and was exposed to 1 μmol/L osimertinib for 72 hours. Apoptosis was measured by flow cytometry. H, KG-1 and Kasumi-1 cells were infected with CD34-targeting CRISPR-Cas9 to deplete endogenous CD34 and then infected with plasmids encompassing WT, C199S, or C199S/C177S mutant CD34. These cells were treated with 2 μmol/L osimertinib for 72 hours and apoptosis was determined by flow cytometry. *, P < 0.05; ***, P < 0.001, between the line-pointed group. EV, empty vector; sgCD34, specific guide CD34; sgNS, specific guide nonspecific.
Figure 4. Osimertinib directly binds to CD34 protein. A, Chemical structure of biotin-tagged osimertinib. B, Pulldown assays were conducted using biotin-osimertinib against recombinant CD34 (rCD34) in the presence/absence of free osimertinib as a competitor. C, Pulldown assays were conducted using biotin-osimertinib against KG-1 cell lysates in the presence/absence of free osimertinib as a competitor. D, MS/MS analysis of the cysteine 199 (C199) tryptic peptide of rCD34 protein incubated with (bottom) or without (top) osimertinib for 30 minutes. E, Predicted conformations of compound osimertinib (magenta) and ibrutinib (cyan) in the binding pocket of CD34. The protein of CD34 is shown in wheat surface and cartoon. Compounds are shown as sticks. Cys177 and Cys199 of CD34 are shown as sticks. The dark dash lines show the distance between Cys199/Cys177 to the atom that is involved in Michael addition (in dash cycles). F, KG-1, Kasumi-1, and primary AML cells were infected with CD34-targeting CRISPR-Cas9 to deplete CD34 expression. Expression of CD34 was analyzed with immunoblot assay. G, CD34 was knocked out by CRISPR-Cas9 system in CD34+ cells purified from patients with AML (n = 3) and was exposed to 1 μmol/L osimertinib for 72 hours. Apoptosis was measured by flow cytometry. H, KG-1 and Kasumi-1 cells were infected with CD34-targeting CRISPR-Cas9 to deplete endogenous CD34 and then infected with plasmids encompassing WT, C199S, or C199S/C177S mutant CD34. These cells were treated with 2 μmol/L osimertinib for 72 hours and apoptosis was determined by flow cytometry. *, P < 0.05; ***, P < 0.001, between the line-pointed group. EV, empty vector; sgCD34, specific guide CD34; sgNS, specific guide nonspecific.CC BY-NC-ND · PubMed Central
Figure 5. Osimertinib impairs interaction between CD34 and the Src protein kinase. A–C, IP assays were conducted using antibodies against Src or CD34 in KG-1, Kasumi-1, and primary CD34+ AML cells. *, the heavy chain of IgG. D, Immunofluorescent staining of Src and CD34 in KG-1 and Kasumi-1. E, IP assay was conducted using antibody against CD34 in primary CD34+ AML cells treated with/without osimertinib. F and G, Kasumi-1 cells were infected with flag-tagged WT (F) or C199S mutant (G) CD34 and then treated with/without osimertinib. IP assay was conducted using anti-Flag antibody. H, Recombinant CD34 peptide (aa324–352) was incubated with Src (middle) or Lyn (bottom), followed by MS/MS analysis. Total ion chromatogram (TIC, sum of MS1 intensities over time) and fragment-ion spectra (MS2, MS/MS) for the major peaks in the TIC-MS1 spectrum of nonphosphorylated peptides (left) and phosphorylated peptides (right) are shown. The b ions and y ions are labeled in blue and red, respectively. I, KG-1 cells were infected with CD34-targeting CRISPR-Cas9 to deplete CD34 expression, followed by overexpression with flag-tagged WT or Y329F mutant, and cell proliferation was evaluated. J and K, Immunoblot analysis showing activity of the STAT3, AKT, ERK, Src in response to osimertinib (1 μmol/L, 72 hours) in primary CD34+ or CD34− cells (J) or KG-1 and Kasumi-1 cells (2 μmol/L, 72 hours; K). L, Primary CD34+ cells purified from patients with AML (n = 3) were treated with 1 μmol/L osimertinib, 2 μmol/L saracatinib, or osimertinib plus saracatinib (combo), and apoptosis was measured by Annexin V/PI staining. M, Primary CD34+ AML cells were treated with 1 μmol/L osimertinib, 1 μmol/L stattic, or osimertinib plus stattic (combo), and apoptosis was measured by Annexin V/PI staining. Quantified apoptotic cells are shown. **, P < 0.005 between the line-pointed group.
Figure 5. Osimertinib impairs interaction between CD34 and the Src protein kinase. A–C, IP assays were conducted using antibodies against Src or CD34 in KG-1, Kasumi-1, and primary CD34+ AML cells. *, the heavy chain of IgG. D, Immunofluorescent staining of Src and CD34 in KG-1 and Kasumi-1. E, IP assay was conducted using antibody against CD34 in primary CD34+ AML cells treated with/without osimertinib. F and G, Kasumi-1 cells were infected with flag-tagged WT (F) or C199S mutant (G) CD34 and then treated with/without osimertinib. IP assay was conducted using anti-Flag antibody. H, Recombinant CD34 peptide (aa324–352) was incubated with Src (middle) or Lyn (bottom), followed by MS/MS analysis. Total ion chromatogram (TIC, sum of MS1 intensities over time) and fragment-ion spectra (MS2, MS/MS) for the major peaks in the TIC-MS1 spectrum of nonphosphorylated peptides (left) and phosphorylated peptides (right) are shown. The b ions and y ions are labeled in blue and red, respectively. I, KG-1 cells were infected with CD34-targeting CRISPR-Cas9 to deplete CD34 expression, followed by overexpression with flag-tagged WT or Y329F mutant, and cell proliferation was evaluated. J and K, Immunoblot analysis showing activity of the STAT3, AKT, ERK, Src in response to osimertinib (1 μmol/L, 72 hours) in primary CD34+ or CD34− cells (J) or KG-1 and Kasumi-1 cells (2 μmol/L, 72 hours; K). L, Primary CD34+ cells purified from patients with AML (n = 3) were treated with 1 μmol/L osimertinib, 2 μmol/L saracatinib, or osimertinib plus saracatinib (combo), and apoptosis was measured by Annexin V/PI staining. M, Primary CD34+ AML cells were treated with 1 μmol/L osimertinib, 1 μmol/L stattic, or osimertinib plus stattic (combo), and apoptosis was measured by Annexin V/PI staining. Quantified apoptotic cells are shown. **, P < 0.005 between the line-pointed group.CC BY-NC-ND · PubMed Central
Figure 6. CD34 is an adverse prognosis marker in AML and associates with specific pathogenic events. A, Differences in OS in de novo patients with AML from the BeatAML dataset (n = 200; left) and TCGA dataset (n = 173; right) by expression of CD34. P values, HRs, and 95% confidence interval (CI) are shown from univariate Cox analysis. B, Differences in OS in de novo patients with AML from the BeatAML dataset (n = 200) by combination of CD34 expression with presence of FLT3, NPM1, CEBPA, and CBF fusion. P values, HRs, and 95% CI are for the CD34 high expression from the multivariate Cox analysis. CBF fusion, RUNX1-RUNX1T1 fusion or CBFB-MYH11 fusion. C, Landscape and percentage of mutations and fusions in patients with AML with high or low CD34 expression level. D and E, RNA-seq and quantitative proteomics analysis of sorted CD34+ cells samples collected from de novo patients with AML and healthy donors (Normal). The mRNA (D) and protein (E) expression level of CD34 are shown. F, HALLMARK genesets from the GSEA analysis of RNA-seq and quantitative proteomic data of CD34+ cells from patients with AML versus normal donors. G, GSEA for complement and DNA repair pathways in AML versus normal samples.
Figure 6. CD34 is an adverse prognosis marker in AML and associates with specific pathogenic events. A, Differences in OS in de novo patients with AML from the BeatAML dataset (n = 200; left) and TCGA dataset (n = 173; right) by expression of CD34. P values, HRs, and 95% confidence interval (CI) are shown from univariate Cox analysis. B, Differences in OS in de novo patients with AML from the BeatAML dataset (n = 200) by combination of CD34 expression with presence of FLT3, NPM1, CEBPA, and CBF fusion. P values, HRs, and 95% CI are for the CD34 high expression from the multivariate Cox analysis. CBF fusion, RUNX1-RUNX1T1 fusion or CBFB-MYH11 fusion. C, Landscape and percentage of mutations and fusions in patients with AML with high or low CD34 expression level. D and E, RNA-seq and quantitative proteomics analysis of sorted CD34+ cells samples collected from de novo patients with AML and healthy donors (Normal). The mRNA (D) and protein (E) expression level of CD34 are shown. F, HALLMARK genesets from the GSEA analysis of RNA-seq and quantitative proteomic data of CD34+ cells from patients with AML versus normal donors. G, GSEA for complement and DNA repair pathways in AML versus normal samples.CC BY-NC-ND · PubMed Central
Figure 7. Effects of osimertinib in human AML and CML PDX models. A, Diagram of experimental design. B, Flow cytometry analyses of human CD45, CD33, and CD34 (hCD45, hCD33, and hCD34, respectively) expression in mouse bone marrow were used to assess engraftment of AML cells. The isotype controls were used to define the gating strategy. C, Percentages of hCD45+ and hCD33+ cells in the bone marrow are shown. D, Diagram of experimental design. E, Representative analyses of human CD34 and mouse CD45 (hCD34 and mCD45, respectively) expression in mouse bone marrow. Right, survival curves of PDX mice. F, CD34+ cells purified from BMMCs of healthy donors were treated with indicated concentrations of osimertinib for 72 hours. Cell apoptosis was quantified by Annexin V/PI staining. Cell viability measured by trypan blue and quantified Annexin V+PI− and Annexin V+PI+ cells (n = 5) are shown. G and H, Colony-forming unit assay of CD34+ AML and normal cells treated with indicated concentrations of osimertinib for 72 hours. Representative image of clones of normal CD34+ cells treated with 1 μmol/L osimertinib (G) and colony numbers (H) are shown. I, The AML and normal CD34+ cells were treated with osimertinib from 0.1 nmol/L to 100 μmol/L and the IC50 curve was constructed. J, Representative analyses of human and mouse CD45 (hCD45 and mCD45, respectively) expression in mouse bone marrow. Bottom, percentages of hCD45+ cells in the bone marrow at 16 weeks. K, White blood cell (WBC) and red blood cell (RBC) counts of AML patient-#1. L, Microscopic appearance of peripheral blood (PB) and bone marrow (BM) smear of AML patient-#1. Day 0 was defined as the day that osimertinib was started. M, White blood cell and platelet counts of AML patient-#2. N, Microscopic appearance of peripheral blood and bone marrow smear of AML patient-#2. O, A model proposing the mechanism by which osimertinib induces apoptosis through CD34-dependent and -independent ways.
Figure 7. Effects of osimertinib in human AML and CML PDX models. A, Diagram of experimental design. B, Flow cytometry analyses of human CD45, CD33, and CD34 (hCD45, hCD33, and hCD34, respectively) expression in mouse bone marrow were used to assess engraftment of AML cells. The isotype controls were used to define the gating strategy. C, Percentages of hCD45+ and hCD33+ cells in the bone marrow are shown. D, Diagram of experimental design. E, Representative analyses of human CD34 and mouse CD45 (hCD34 and mCD45, respectively) expression in mouse bone marrow. Right, survival curves of PDX mice. F, CD34+ cells purified from BMMCs of healthy donors were treated with indicated concentrations of osimertinib for 72 hours. Cell apoptosis was quantified by Annexin V/PI staining. Cell viability measured by trypan blue and quantified Annexin V+PI− and Annexin V+PI+ cells (n = 5) are shown. G and H, Colony-forming unit assay of CD34+ AML and normal cells treated with indicated concentrations of osimertinib for 72 hours. Representative image of clones of normal CD34+ cells treated with 1 μmol/L osimertinib (G) and colony numbers (H) are shown. I, The AML and normal CD34+ cells were treated with osimertinib from 0.1 nmol/L to 100 μmol/L and the IC50 curve was constructed. J, Representative analyses of human and mouse CD45 (hCD45 and mCD45, respectively) expression in mouse bone marrow. Bottom, percentages of hCD45+ cells in the bone marrow at 16 weeks. K, White blood cell (WBC) and red blood cell (RBC) counts of AML patient-#1. L, Microscopic appearance of peripheral blood (PB) and bone marrow (BM) smear of AML patient-#1. Day 0 was defined as the day that osimertinib was started. M, White blood cell and platelet counts of AML patient-#2. N, Microscopic appearance of peripheral blood and bone marrow smear of AML patient-#2. O, A model proposing the mechanism by which osimertinib induces apoptosis through CD34-dependent and -independent ways.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Xia, L., Liu, J.-Y., Yang, M.-Y., Zhang, X.-H., Jiang, Y., Yin, Q.-Q., Luo, C.-H., Liu, H.-C., Kang, Z.-J., Zhang, C.-T., Gao, B.-B., Zhou, A.-W., Cai, H.-Y., Waller, E. K., Yan, J.-S., & Lu, Y.
Affiliations
  • 1Institute of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • Shanghai Jiao Tong University (CN)
  • 3Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Liaoning, China.
  • Dalian Medical University (CN)
  • 5Shanghai Institute for Advanced Immunochemical Studies, Shanghai Tech University, Shanghai, China.
  • 4Department of Hematology, Liaoning Medical Center for Hematopoietic Stem-Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem-Cell Transplantation and Translational Medicine, Dalian Key Laboratory of Hematology, the Second Hospital of Dalian Medical University, Dalian, China.
  • 6Basic Medical Institute, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Winship Cancer Institute (US)
Corresponding author
Lu, Ying
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2023-12-14
Volume
84
Issue
3
Pages
479-492
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-23-1632
PMC
PMC10831336
OpenAlex
W4389732350
Cited by
5
References
4
Citations by year
2025: 3 · 2024: 2
FWCI
1.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Research (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (82170179, 81970131, 81370652, 81770146, 32171431)
  • Science and Technology Commission of Shanghai Municipality (22S11900400)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
osimertinib, CD34, acute myeloid leukemia, chronic myeloid leukemia, covalent binding, apoptosis, Src family kinases, STAT3 signaling, synthetic lethality, prognostic factors, patient-derived xenografts, compassionate use
MeSH terms
Acrylamides, Aniline Compounds, Carcinoma, Non-Small-Cell Lung, Humans, Indoles, Lung Neoplasms, Pyrimidines, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Antigens, CD34, Myeloid Progenitor Cells, Proteomics, Cell Proliferation, ErbB Receptors

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