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1.
Blood Cancer Discov ; 4(5): 394-417, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37470778

ABSTRACT

Cancer initiation is orchestrated by an interplay between tumor-initiating cells and their stromal/immune environment. Here, by adapted single-cell RNA sequencing, we decipher the predicted signaling between tissue-resident hematopoietic stem/progenitor cells (HSPC) and their neoplastic counterparts with their native niches in the human bone marrow. LEPR+ stromal cells are identified as central regulators of hematopoiesis through predicted interactions with all cells in the marrow. Inflammatory niche remodeling and the resulting deprivation of critical HSPC regulatory factors are predicted to repress high-output hematopoietic stem cell subsets in NPM1-mutated acute myeloid leukemia (AML), with relative resistance of clonal cells. Stromal gene signatures reflective of niche remodeling are associated with reduced relapse rates and favorable outcomes after chemotherapy across all genetic risk categories. Elucidation of the intercellular signaling defining human AML, thus, predicts that inflammatory remodeling of stem cell niches drives tissue repression and clonal selection but may pose a vulnerability for relapse-initiating cells in the context of chemotherapeutic treatment. SIGNIFICANCE: Tumor-promoting inflammation is considered an enabling characteristic of tumorigenesis, but mechanisms remain incompletely understood. By deciphering the predicted signaling between tissue-resident stem cells and their neoplastic counterparts with their environment, we identify inflammatory remodeling of stromal niches as a determinant of normal tissue repression and clinical outcomes in human AML. See related commentary by Lisi-Vega and Méndez-Ferrer, p. 349. This article is featured in Selected Articles from This Issue, p. 337.


Subject(s)
Hematopoietic Stem Cells , Leukemia, Myeloid, Acute , Humans , Bone Marrow , Leukemia, Myeloid, Acute/genetics , Hematopoiesis/genetics , Stromal Cells
2.
Hemasphere ; 7(2): e823, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36741354

ABSTRACT

Mesenchymal stem cells (MSCs) play pivotal roles in tissue (re)generation. In the murine bone marrow, they are thought to reside within the Sca-1+ CD51+ bone marrow stromal cell population. Here, using scRNAseq, we aimed to delineate the cellularheterogeneity of this MSC-enriched population throughout development. At the fetal stage, the MSC population is relatively homogeneous with subsets predicted to contain stem/progenitor cells, based on transcriptional modeling and marker expression. These subsets decline in relative size throughout life, with postnatal emergence of specialized clusters, including hematopoietic stem/progenitor cell (HSPC) niches. In fetal development, these stromal HSPC niches are lacking, but subsets of endothelial cells express HSPC factors, suggesting that they may provide initial niches for emerging hematopoiesis. This cellular taxonomy of the MSC population upon development is anticipated to provide a resource aiding the prospective identification of cellular subsets and molecular mechanisms driving bone marrow (re)generation.

3.
Exp Hematol ; 105: 32-38.e2, 2022 01.
Article in English | MEDLINE | ID: mdl-34800603

ABSTRACT

Chemotherapy-induced bone marrow (BM) injury is a significant cause of morbidity and mortality in acute myeloid leukemia (AML). Time to hematologic recovery after standard ("7 + 3") myeloablative chemotherapy can vary considerably among patients, but the factors that drive or predict BM recovery remain incompletely understood. Here, we assessed the composition of innate and adaptive immune subsets in the regenerating BM (day 17) after induction chemotherapy and related it to hematologic recovery in AML. T cells, and in particular the CD4 central memory (CD4CM) T-cell subset, were significantly enriched in the BM after chemotherapy, suggesting the relative chemoresistance of cells providing long-term memory for systemic pathogens. In contrast, B cells and other hematopoietic subsets were depleted. Higher frequencies of the CD4CM T-cell subset were associated with delayed hematopoietic recovery, whereas a high frequency of natural killer (NK) cells was related to faster recovery of neutrophil counts. The NK/CD4CM ratio in the BM after chemotherapy was significantly associated with the time to subsequent neutrophil recovery (Spearman's ρ = -0.723, p < 0.001, false discovery rate <0.01). The data provide novel insights into adaptive immune cell recovery after injury and identify the NK/CD4CM index as a putative predictor of hematopoietic recovery in AML.


Subject(s)
Adaptive Immunity/drug effects , Antineoplastic Agents/adverse effects , Immunity, Innate/drug effects , Leukemia, Myeloid, Acute/drug therapy , Adult , Aged , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Cells, Cultured , Female , Humans , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Leukemia, Myeloid, Acute/immunology , Male , Middle Aged , Young Adult
4.
Cell Stem Cell ; 28(4): 653-670.e11, 2021 04 01.
Article in English | MEDLINE | ID: mdl-33561425

ABSTRACT

Bone marrow stromal cells (BMSCs) play pivotal roles in tissue maintenance and regeneration. Their origins, however, remain incompletely understood. Here we identify rare LNGFR+ cells in human fetal and regenerative bone marrow that co-express endothelial and stromal markers. This endothelial subpopulation displays transcriptional reprogramming consistent with endothelial-to-mesenchymal transition (EndoMT) and can generate multipotent stromal cells that reconstitute the bone marrow (BM) niche upon transplantation. Single-cell transcriptomics and lineage tracing in mice confirm robust and sustained contributions of EndoMT to bone precursor and hematopoietic niche pools. Interleukin-33 (IL-33) is overexpressed in subsets of EndoMT cells and drives this conversion process through ST2 receptor signaling. These data reveal generation of tissue-forming BMSCs from mouse and human endothelial cells and may be instructive for approaches to human tissue regeneration.


Subject(s)
Bone Marrow , Hematopoietic Stem Cell Transplantation , Animals , Bone Marrow Cells , Endothelial Cells , Endothelium , Hematopoietic Stem Cells , Mice , Stromal Cells
6.
Elife ; 52016 10 19.
Article in English | MEDLINE | ID: mdl-27759562

ABSTRACT

TP53 truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show that TP53 exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis. Functionally and molecularly, these p53 mutants resemble the naturally occurring alternative p53 splice variant, p53-psi. Accordingly, these mutants can localize to the mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD). Together, our studies reveal that TP53 exon-6 truncating mutations, contrary to current beliefs, act beyond p53 loss to promote tumorigenesis, and could inform the development of strategies to target cancers driven by these prevalent mutations.


Subject(s)
Mutation , Neoplasms/pathology , Sequence Deletion , Tumor Suppressor Protein p53/genetics , Animals , Cell Line, Tumor , Cell Proliferation , Cell Survival , Cyclophilins/metabolism , Disease Models, Animal , Heterografts , Humans , Mice, Nude , Mitochondrial Membranes/physiology , Neoplasm Metastasis , Permeability , Protein Isoforms
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