Single-cell RNA Sequencing Reveals Novel Cellular Factors for Response to Immunosuppressive Therapy in Aplastic Anemia

Abstract

Aplastic anemia (AA) is a lethal hematological disorder; however, its pathogenesis is not fully understood. Although immunosuppressive therapy (IST) is a major treatment option for AA, one-third of patients do not respond to IST and its resistance mechanism remains elusive. To understand AA pathogenesis and IST resistance, we performed single-cell RNA sequencing (scRNA-seq) of bone marrow (BM) from healthy controls and patients with AA at diagnosis. We found that CD34+ early-stage erythroid precursor cells and PROM1+ hematopoietic stem cells were significantly depleted in AA, which suggests that the depletion of CD34+ early-stage erythroid precursor cells and PROM1+ hematopoietic stem cells might be one of the major mechanisms for AA pathogenesis related with BM-cell hypoplasia. More importantly, we observed the significant enrichment of CD8+ T cells and T cell–activating intercellular interactions in IST responders, indicating the association between the expansion and activation of T cells and the positive response of IST in AA. Taken together, our findings represent a valuable resource offering novel insights into the cellular heterogeneity in the BM of AA and reveal potential biomarkers for IST, building the foundation for future precision therapies in AA.

Heterogeneity of platelets and their responses

“…Future directions in this still-understudied area of platelet heterogeneity abound. For instance, although recent single-cell omics studies explore the cellular landscape in various hematologic disorders [ [125] , [126] , [127] , [128] ], these have largely been limited to measuring single modalities at a time. Multiomic investigations of each of progenitor stem cells, megakaryocytes, and platelets from the same patient are currently lacking.…”

The state of the art in the treatment of severe aplastic anemia: immunotherapy and hematopoietic cell transplantation in children and adults

“…Evaluated biomarkers potentially predictive of better response to IST are as follows: baseline absolute lymphocyte count ≥1 × 10 9 / L; absolute reticulocyte count ≥25 × 10 9 /L; PIGA, BCOR, and BCORL mutations. There are also potential biomarker candidates requiring clinical validation: predominance of memory/activated phenotype of T regulatory cells; increased intracellular IFN-g levels in circulating T cells; IFN-g +874T/A gene polymorphism; bone marrow enrichment of CD8 + T cells and T cell-activating intercellular interactions; and miR-150-5p expression (31, [133][134][135][136][137][138]. Poor response to IST might be expected with an undetectable PNH clone and a shorter telomere length, and detection of adverse genetic mutations: ASXL1, DNMT3A, RUNX1, TP53, but also with TPO plasma levels of >1,796.7 pg/ml (32, 139, 140).…”