{"doi":"10.1002/ajh.27627","title":"Recipient Cells Are the Source of Hematologic Malignancies After Graft Failure and Mixed Chimerism in Adults With <scp>SCD</scp>","abstract":"Hematopoietic cell transplant (HCT) is the only curative option for individuals with sickle cell disease (SCD). Traditionally, young patients with a human leukocyte antigen (HLA)-matched donor received myeloablative conditioning followed by HCT to completely replace recipient hematopoietic cells with healthy donor cells (full donor chimerism). Unfortunately, less than 15% of patients have an HLA-matched sibling donor (MSD). Conversely, haploidentical (haplo) HCT greatly expands the donor pool. Moreover, adults with SCD and overt organ damage cannot tolerate myeloablative conditioning. Therefore, we developed a non-myeloablative approach that could be applied to such patients. This approach initially aimed at achieving a state of mixed donor and recipient chimerism, where the hematopoietic system is constituted by both the donor's and recipient's cells. Indeed, we have reported that 20% donor myeloid chimerism is sufficient to reverse the SCD phenotype because of a significant difference in the life span of healthy versus sickled red blood cells [1]. In 2023, the FDA approved two additional potentially curative therapies. First, Lyfgenia, by Bluebird Bio, uses a lentiviral vector to genetically modify hematopoietic stem and progenitor cells (HSPCs) to produce HbAT87Q, which functions similarly to HbA. Second, Casgevy, a clustered, regularly interspaced palindromic repeats-associated protein-9 nuclease (CRISPR-Cas9) gene-edited therapy, reactivates the production of fetal hemoglobin. Both therapies would still require myeloablative conditioning, which limits its application to younger patients with no significant organ damage. Two studies have reported an increased relative risk of leukemia development in patients with SCD, though the absolute risk is low [2]. Moreover, several groups have reported an increased risk of leukemia development after curative therapies, mainly after graft failure in SCD patients [2]. We have recently reported that eight out of 120 patients who received nonmyeloablative allogeneic HCT developed hematologic malignancies (HMs) between 4 months and 9 years post-HCT: five developed aggressive therapy-related myeloid neoplasms (myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)), one T-cell acute lymphoblastic leukemia (ALL), one chronic myeloid leukemia, and one mantle cell lymphoma [2]. In addition, two adult Group A patients from the bluebird bio study subsequently developed AML [2]. Leukemia development has been associated with the acquisition of somatic mutations, which accumulate with aging in a condition known as clonal hematopoiesis (CH). Somatic mutations in genes involved in stem cell self-renewal or cellular differentiation pathways bestow a considerable survival advantage or fitness upon the mutant hemopoietic clone, resulting in its significant expansion compared with nonmutant cells [3]. Whole exome sequencing analysis showed that SCD is associated with increased prevalence of CH [4]; among the most commonly mutated genes is TP53, which comes in second, after DNMT3A, accounting for 13% of all CH mutations in SCD [3]. CH mutations have been reported in patients with SCD who developed HMs after curative therapies [3, 5]. The origin of the HMs, donor- or recipient-derived, has not been previously reported. Since most of those HMs developed after graft failure, we hypothesized that the origin of the leukemia-initiating cells (LICs) is the recipient due to a survival advantage of HSPCs containing somatic mutations that transform with genotoxic conditioning followed by erythropoietic stress. In this report, we investigated the source of leukemic blasts and MDS mononuclear cells (MNCs) by analyzing the chimerism levels in peripheral blood (PB) or bone marrow (BM) cells from patients who developed HMs post-HCT. We utilized frozen biospecimens from patients diagnosed with the most aggressive HMs after HCT. All samples were collected under an NHLBI IRB-approved protocol, clinicaltrials.gov ","journal":"American Journal of Hematology","year":2025,"id":522676,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1125191,"name":"Emily Limerick","orcid":"0000-0003-1591-2451","position":1,"is_corresponding":false},{"id":314731,"name":"Matthew M. Hsieh","orcid":"0000-0002-3706-6615","position":2,"is_corresponding":false},{"id":1134595,"name":"Kalpana Upadhyaya","orcid":null,"position":3,"is_corresponding":false},{"id":239790,"name":"Xin Xu","orcid":"0000-0003-1163-9304","position":4,"is_corresponding":false},{"id":1382277,"name":"Oswald Phang","orcid":null,"position":5,"is_corresponding":false},{"id":1394158,"name":"Jean Pierre Kambala Mukendi","orcid":"0000-0002-8383-6246","position":6,"is_corresponding":false},{"id":218270,"name":"Katherine R. Calvo","orcid":"0000-0002-0771-4191","position":7,"is_corresponding":false},{"id":1064373,"name":"Maria Lopez‐Ocasio","orcid":null,"position":8,"is_corresponding":false},{"id":271933,"name":"Pradeep K. Dagur","orcid":"0000-0002-4491-0853","position":9,"is_corresponding":false},{"id":314732,"name":"Courtney D. Fitzhugh","orcid":"0000-0002-5306-7167","position":10,"is_corresponding":false},{"id":465769,"name":"Mohamed Ashraf Ali","orcid":"0000-0003-2352-2760","position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-19T02:49:54.058858Z","pmid":"39912461","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}