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. 2023 Aug 30;621(7978):404–414. doi: 10.1038/s41586-023-06496-5

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Extended Data Fig. 10 — a. Xeno-transplants of CD123^S59 or AAVS1-BE HSPCs co-engrafted with AML PDX-1 and treated with 5M CSL362 CAR-T. b. Representative FACS plots of BM samples from mice engrafted with HSPCs+PDX-1 treated with CSL362 CAR-T or untreated. Plots are pre-gated on total human CD45+; CAR-T cells are identified by CD3 staining, while AML PDX cells are mNeonGreen+. c. CD123 editing on PB (week 8-10) and sorted CD33+/CD19+ BM cells. CD123^S59 N = 6, AAVS1 BE N = 5. Mean ± SD. Statistical comparison by multiple unpaired t-test. d. Bar plots showing the % of AML PDX cells within hCD45+CD3- BM cells. Mean ± SD. e. Percentage of CD3+ cells within hCD45+mNeonGreen- BM cells. Mean ± SD. One-way ANOVA. f. Absolute counts of total hCD45+3-mNeonGreen- cells in the BM. Mean ± SD. One-way ANOVA. g. Percentage of pro-B cells (CD19+10-34-) within human CD45+3-mNeonGreen- BM cells. Mean ± SD. Statistical comparison of CD123^S59 vs AAVS1-BE conditions by one-way ANOVA. h. Left: representative FACS plots showing depletion of BM myeloid cells (CD33/66b+19-, highlighted by the orange gate) by CSL362 CAR-T in mice transplanted with CD123^S59 or AAVS1 BE HSPCs. Right: representative FACS plots showing depletion of granulocytes (PMN, CD33/66b+19-14-SSC^high, orange gate) i. Bar plots showing the % of total myeloid cells (CD33/66b+19- within hCD45+ cells), (j) PMN (CD33/66b+19- within CD33/66b+19- cells), (k) immature PMN (CD33/66b+19-14-10-11c-SSC^high within CD33/66b+19- cells). Mean ± SD. Statistical comparison of CD123^S59 vs AAVS1 BE conditions by one-way ANOVA. l. Representative flow cytometry plots showing loss of dendritic cells (DC) subsets by CSL362 CAR-T in mice transplanted with CD123^S59 or AAVS1 BE HSPCs. Left: conventional DC (cDC, CD33/66b+14-11c+FLT3+SSC^low), plots are gated on CD33/66b+14-SSC^low cells. Right: plasmacytoid DC (pDC, CD33/66b+14-11c-FLT3+CD123^highSSC^low), plots are gated on CD33/66b+14-11c-SSC^low cells. m. and n. Percentage of cDC and pDC within hCD45+3-mNeonGreen- cells, respectively. o. Percentage of lineage-CD34+ progenitors within hCD45+3-mNeonGreen- cells. Mean ± SD. Statistical comparison of CD123^S59 vs AAVS1-BE conditions by one-way ANOVA. p. Lineage-negative CD34+ progenitors are depleted by CSL362 CAR-T and protected by CD123^S59 BE. Left, representative flow cytometry plots of lineage-negative cells (mNeonGreen-CD3-19-14-11c-56-) with gating of CD34+ progenitors. Right, representative flow cytometry plots of lin-CD34+38-10- cells with gating of HSC (CD45RA-90+), MPP (CD45RA-90-), LMPP (CD45RA+90-) subsets. q and r. Absolute counts of progenitors (q) and myeloid and lymphoid lineage subsets (r) in the BM. Untreated mice are pooled together (grey bars), while CSL362-treated CD123^S59 and AAVS1-BE mice are reported in pink and blue, respectively. The fold change in absolute counts (CD123^S59/ AAVS1) for CAR treated groups is reported above each population bar plot. Mean ± SD. One-way ANOVA with multiple comparison. FDR-adjusted p-values of the comparison between CD123^S59 vs AAVS1 BE treated with 4G8-CAR are reported (p < 0.05 in bold).