S72 reduced cytotoxic capability against acute myeloid leukemia and CCUS cells in functional in vitro assays, and this capability was not rescued by prolonged culture with feeder cells and interleukin 2. These results suggest that CCUS NK cells are irreversibly dysfunctional. Consistent with this observation, high-throughput single-cell targeted DNA and surface protein sequencing analysis using the Mission Bio Tapestri Platform showed that NK cells isolated from 5 CCUS patients with different genetic alterations were part of the mutant clone, which suggests that mutant HSPCs can evade immune surveillance owing to molecular and functional defects in the immune system. These data demonstrate that CCUS maintenance is the result of multiple biological and cellular alterations impacting the functions of different types of BM cells. Conclusions Our results provide an in-depth analysis of HSPCs and BM cells from CCUS samples at the single-cell level and identify, for the first time, therapeutic interventions to arrest MDS in its early stage, before the disease can have a dismal outcome. Acknowledgments This work was supported by philanthropic contributions to MD Anderson’s AML and MDS Moon Shot Program, and by the P. Evans Foundation. S.C. is a Scholar of the Leukemia and Lymphoma Society. References 1. Will B, Zhou L, Vogler TO, et al. Stem and progenitor cells in myelodysplastic syndromes show aberrant stagespecific expansion and harbor genetic and epigenetic alterations. Blood. Sep 6 2012;120(10):2076-86. doi:10.1182/blood-2011-12-399683 2. Woll PS, Kjallquist U, Chowdhury O, et al. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell. Jun 16 2014;25(6):794-808. doi:10.1016/j.ccr.2014.03.036 3. Mortera-Blanco T, Dimitriou M, Woll PS, et al. SF3B1initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells. Blood. Aug 17 2017;130(7):881890. doi:10.1182/blood-2017-03-776070 4. Chesnais V, Arcangeli ML, Delette C, et al. Architectural and functional heterogeneity of hematopoietic stem/ progenitor cells in non-del(5q) myelodysplastic syndromes. Blood. Jan 26 2017;129(4):484-496. doi:10.1182/ blood-2016-03-707745 5. Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nature reviews Cancer. Jan 2017;17(1):5-19. doi:10.1038/nrc.2016.112 6. Ganan-Gomez I, Yang H, Ma F, et al. Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy. Nature medicine. Mar 3 2022;doi:10.1038/s41591-022-01696-4 7. Xie Z, Zeidan AM. CHIPing away the progression potential of CHIP: A new reality in the making. Blood Rev. Aug 15 2022:101001. doi:10.1016/j.blre.2022.101001 8. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. Jul 2 2015;126(1):9-16. doi:10.1182/blood-2015-03-631747 9. Osman AEWG. When are idiopathic and clonal cytopenias of unknown significance (ICUS or CCUS)? Hematology. 2021;2021(1):399-404. doi:10.1182/ hematology.2021000272 10. Weeks LD, Niroula A, Neuberg D, et al. Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis. NEJM Evidence. 2023;2(5):EVIDoa2200310. doi:doi:10.1056/ EVIDoa2200310 11. Chandel NS, Jasper H, Ho TT, Passegue E. Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat Cell Biol. Aug 2016;18(8):823-32. doi:10.1038/ncb3385 12. Testa U, Labbaye C, Castelli G, Pelosi E. Oxidative stress and hypoxia in normal and leukemic stem cells. Exp Hematol. Jul 2016;44(7):540-60. doi:10.1016/j. exphem.2016.04.012 13. Pietras EM, Mirantes-Barbeito C, Fong S, et al. Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat Cell Biol. Jun 2016;18(6):607-18. doi:10.1038/ncb3346 14. Guo LY, Yang F, Peng LJ, Li YB, Wang AP. CXCL2, a new critical factor and therapeutic target for cardiovascular diseases. Clin Exp Hypertens. Jul 3 2020;42(5):428-437. doi:10.1080/10641963.2019.1693585
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