P1289: DECIPHERING THE CLONAL ARCHITECTURE IN SECONDARY ACUTE MYELOID LEUKEMIA AND DONOR CELL-DERIVED MYELODYSPLASTIC SYNDROME BY SINGLE-CELL MULTI-OMICS ANALYSIS

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Topic: 22. Stem cell transplantation - Clinical Background: Myeloproliferative neoplasms (MPNs) are a group of clonal hematopoietic stem cell diseases. Disease transformation into secondary myelofibrosis and acute myeloid leukemia (AML) negatively impact the outcome of MPNs and are frequently related to the clonal evolution of the disease subclones. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment option for patients with secondary AML (sAML). Donor-derived myelodysplastic syndrome (MDS) is a rare complication of HSCT and the incidence is estimated to be between 0.5% and 3%. Donor MDS can occur due to the transfer of malignant stem cells or pre-malignant clones from the donor to the recipient during HSCT. Aims: This study aimed to decipher the clonal architecture in a patient with JAK2 V617F-mutated essential thrombocythemia transformed to sAML and then developed donor MDS by single-cell multi-omics analysis over multiple treatment time points. Methods: Bulk next-generation sequencing (NGS) and customized Tapestri single-cell multi-omics DNA-protein panels were used to sequence peripheral blood and bone marrow samples at the time of sAML transformation, after complete hematologic remission, after sibling-matched allogeneic HSCT, and after the occurrence of donor MDS. A total of 10,049 cells from 4 samples of the patient were analyzed. Results: The results of bulk NGS revealed that the JAK2 V617F-mutated patient acquired IDH1 R132G and PHF6 I314T mutations at the time of sAML transformation, and all 3 mutations became undetectable after sibling-matched allogeneic HSCT. The results of single-cell multi-omics DNA-protein analysis revealed that the sAML subclone harbored all the 3 mutations (JAK2 V617F/IDH1 R132G and PHF6 I314T) and EZH2 loss. The sAML subclone has a significantly higher expression of CD71 (Figure 1). After sibling-matched allogeneic HSCT, a subclone from the donor cells was found to harbor EZH2 loss but the patient remained in complete remission. After being diagnosed with donor MDS due to progressive thrombocytopenia and bone marrow dysplasia, the patient remained 100% donor-type short tandem repeats. Single-cell multi-omics analysis showed that the donor MDS subclone harbored a TP53 mutation and EZH2 loss, and a JAK2 V617F-mutated subclone was also detected in donor cells. Interestingly, the donor MDS subclone also has a higher CD71 expression. Summary/Conclusion: The clonal architectures of sAML and donor MDS were clearly illustrated by single-cell multi-omics analysis in our study.Keywords: Clonal expansion, MDS, Acute myeloid leukemia, Allogeneic hematopoietic stem cell transplant

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