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2027
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| Online Access: | https://doi.org/10.5281/zenodo.14786669 |
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| author | Koedijk, Joost Heidenreich, Olaf |
| author_facet | Koedijk, Joost Heidenreich, Olaf |
| contents | <p>Bispecific T-cell engagers (BiTEs) have demonstrated remarkable success in treating B cell precursor acute lymphoblastic leukemia, B cell non-Hodgkin’s lymphoma, and multiple myeloma. However, their efficacy in acute myeloid leukemia (AML) has so far been limited. Emerging evidence suggests that BiTE therapy may be more effective in the setting of low tumor burden or minimal residual disease, e.g., in between chemotherapy courses. Yet, it is unclear whether current chemotherapy-based regimens create a bone marrow (BM) microenvironment conducive to BiTE therapy. To address this gap, we performed a comprehensive analysis of the BM lymphocyte compartment in newly diagnosed pediatric AML patients undergoing induction therapy across three international treatment protocols. We observed significant differences in BM lymphocyte frequencies over the course of therapy, with distinct dynamics across protocols. Additionally, we demonstrated that T-cells from pediatric AML patients obtained at end-of-induction one and two are functional and responsive to BiTE therapy. These findings highlight the importance of systematically characterizing the BM immune microenvironment during chemotherapy-based regimens to identify the optimal timing for BiTE therapy. Furthermore, they provide a compelling rationale for exploring the potential of BiTE therapy in between chemotherapy courses in pediatric AML. </p> <p>For this study, we acquired diagnostic bulk RNA-sequencing data generated from bone marrow mononuclear cells (BMMCs) from children with acute myeloid leukemia (AML) at diagnosis (n=51). We also performed bulk RNA-sequencing to generate data for time points in between chemotherapy courses: end of induction 1 (n=21), end of induction 2 (n=21), and end of consolidation (n=6). As a reference, we used and/or conducted bulk RNA-sequencing (data) from age-matched children that did not have leukemia (non-leukemic controls: n=4 were previously published by our group (early-stage rhabdomyosarcoma without bone marrow involvement), PMID=37908360; n=3 were newly generated (healthy siblings of patients undergoing allogeneic hematopoietic stem cell transplantation)). Briefly, total RNA was isolated from BMMCs, and RNA-seq libraries were generated from 300 ng RNA, and sequenced using the NovaSeq 6000 (2x150 bp; Illumina). After pre-processing, RNA-sequencing typically yielded 60-100 million raw reads, which were then aligned to the GRCh38 reference genome using the gene annotations provided by GENCODE version 31. Raw counts were normalized to counts per million (CPM) and used with CIBERSORTx (cibersortx.stanford.edu)and a healthy BM reference, to infer the abundance of lymphoid subsets in the BM. </p> <p>See the metadata sheet for more details on the methods. </p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_14786669 |
| institution | Zenodo |
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| publishDate | 2027 |
| publisher | Zenodo |
| record_format | zenodo |
| spellingShingle | Bone marrow lymphocyte dynamics and immunotherapeutic potential during chemotherapy in pediatric acute myeloid leukemia Koedijk, Joost Heidenreich, Olaf <p>Bispecific T-cell engagers (BiTEs) have demonstrated remarkable success in treating B cell precursor acute lymphoblastic leukemia, B cell non-Hodgkin’s lymphoma, and multiple myeloma. However, their efficacy in acute myeloid leukemia (AML) has so far been limited. Emerging evidence suggests that BiTE therapy may be more effective in the setting of low tumor burden or minimal residual disease, e.g., in between chemotherapy courses. Yet, it is unclear whether current chemotherapy-based regimens create a bone marrow (BM) microenvironment conducive to BiTE therapy. To address this gap, we performed a comprehensive analysis of the BM lymphocyte compartment in newly diagnosed pediatric AML patients undergoing induction therapy across three international treatment protocols. We observed significant differences in BM lymphocyte frequencies over the course of therapy, with distinct dynamics across protocols. Additionally, we demonstrated that T-cells from pediatric AML patients obtained at end-of-induction one and two are functional and responsive to BiTE therapy. These findings highlight the importance of systematically characterizing the BM immune microenvironment during chemotherapy-based regimens to identify the optimal timing for BiTE therapy. Furthermore, they provide a compelling rationale for exploring the potential of BiTE therapy in between chemotherapy courses in pediatric AML. </p> <p>For this study, we acquired diagnostic bulk RNA-sequencing data generated from bone marrow mononuclear cells (BMMCs) from children with acute myeloid leukemia (AML) at diagnosis (n=51). We also performed bulk RNA-sequencing to generate data for time points in between chemotherapy courses: end of induction 1 (n=21), end of induction 2 (n=21), and end of consolidation (n=6). As a reference, we used and/or conducted bulk RNA-sequencing (data) from age-matched children that did not have leukemia (non-leukemic controls: n=4 were previously published by our group (early-stage rhabdomyosarcoma without bone marrow involvement), PMID=37908360; n=3 were newly generated (healthy siblings of patients undergoing allogeneic hematopoietic stem cell transplantation)). Briefly, total RNA was isolated from BMMCs, and RNA-seq libraries were generated from 300 ng RNA, and sequenced using the NovaSeq 6000 (2x150 bp; Illumina). After pre-processing, RNA-sequencing typically yielded 60-100 million raw reads, which were then aligned to the GRCh38 reference genome using the gene annotations provided by GENCODE version 31. Raw counts were normalized to counts per million (CPM) and used with CIBERSORTx (cibersortx.stanford.edu)and a healthy BM reference, to infer the abundance of lymphoid subsets in the BM. </p> <p>See the metadata sheet for more details on the methods. </p> |
| title | Bone marrow lymphocyte dynamics and immunotherapeutic potential during chemotherapy in pediatric acute myeloid leukemia |
| url | https://doi.org/10.5281/zenodo.14786669 |