Biology subjects

Usukhbayar, B.

Publications and source records attributed to Usukhbayar, B..

5 recordsLinked to original sources

bioRxiv2024

Rapid clonal selection within early hematopoietic cell compartments presages outcome to ivosidenib combination therapy

Acquired resistance to targeted non-intensive therapies is common in myeloid malignancies. Yet, key questions remain as to how rapidly resistant clones are selected by treatment and in which hematopoietic cell compartments clonal selection occurs. To address this gap, we studied clonal responses to ivosidenib + venetoclax {+/-} azacitidine combination therapy in 8 patients with IDH1-mutant myeloid malignancy. Whilst all 8 patients initially responded to treatment, 6 relapsed and 2 remained in sustained remission for > 4 years. To study longitudinal clonal dynamics through hematopoietic differentiation, we performed high-sensitivity single-cell genotyping in index-sorted sequential patient samples. In all patients who relapsed, therapy-resistant clones were selected rapidly, within 1-3 treatment cycles, at times when hematopoiesis was still largely sustained by either normal or pre-leukemic cells. Selection of therapy-resistant clones preceded overt treatment failure by months or even years. Relapse was associated either with clones harboring newly-detected myeloid driver mutations or expansion of minor pre-existing clones that had reduced fitness prior to treatment. In both cases, resistant clones were selected within immature cell populations previously shown to contain leukemic stem cell (LSC) potential, preceding malignant expansion of these compartments by immunophenotyping. In contrast, in both patients remaining in remission, leukemic clones were eradicated and rapidly replaced by clonal and wild-type hematopoiesis. These observations suggest that, in patients treated with non-intensive ivosidenib combination therapy, rapid clonal selection occurs in populations with LSC potential, where failure to eliminate either genetically evolved or persistent leukemic clones ultimately leads to relapse. Key points- Rapid selection of leukemic clones occurs within small populations with LSC potential, months or years prior to relapse. - Rapid eradication of leukemic clones leads to sustained remission in the context of ivosidenib combination therapy.

cancer biology↗

bioRxiv2023

Selective advantage of mutant stem cells in clonal hematopoiesis occurs by attenuating the deleterious effects of inflammation and aging

Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSC) acquire mutations in genes, including DNMT3A and TET2, conferring a competitive advantage through a mechanism that remains unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on CH bone marrow samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared to HSC from non-CH samples, revealing a non-cell autonomous mechanism. However, DNMT3A and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are more resistant to the deleterious impact of inflammation and aging.

cancer biology↗

bioRxiv2023

Dysregulation of chromatin via H3K27 methylation underpins differentiation arrest in Isocitrate dehydrogenase-mutant Acute Myeloid Leukaemia.

Dysregulation of cellular differentiation is a hallmark of cancer. Isocitrate dehydrogenase (IDH) is commonly mutated multiple cancers including glioma, cholangiocarcinoma, lymphoma and Acute Myeloid Leukaemia (AML). Mutant IDH generates d-2-hydroxyglutarate that inhibits enzymes including Jumonji histone demethylases and TET2. Using primary human IDH2-mutant AML cells as a model, single cell RNA-seq and ATAC-seq, we demonstrated the continuum of cell states during restoration of neutrophilic differentiation to leukaemic progenitors by Enasidenib, a mutant IDH2 inhibitor. In cells which ultimately differentiate, there is co-expression of competing GATA2/RUNX3/SOX4-driven stem-progenitor and pro-differentiation EGR1/JUN/FOS programmes, followed by expression of cell cycle and terminal neutrophil programmes involving CEBP family and SPI1/PU.1. Genes upregulated during differentiation display loss of H3K27me3 in bivalent chromatin but not of H3K4me3, while downregulated genes are enriched for PRC2/EZH2 targets. In contrast to previous reports of a TET2-dependent mechanism for IDH-mutations, we observed only a modest link between promoter DNA CpG methylation and gene expression. For the first time in primary AML, we describe the lifting of differentiation block by de-repression of pro-differentiation genes through modulation of H3K27 demethylation in bivalent chromatin, and thus highlight a novel and important mechanism in how IDH mutations disrupt cell fates in cancer.

cancer biology↗

bioRxiv2021

A simple and direct method to define clonal selection in somatic mosaicism

As DNA variants accumulate in somatic stem cells, become selected or evolve neutrally, they may ultimately alter tissue function. When, and how, selection occurs in homeostatic tissues is incompletely understood. Here, we introduce SCIFER, a scalable method that identifies selection in an individual tissue, without requiring knowledge of the underlying driver event. Moreover, SCIFER infers the self-renewal and mutation dynamics of the tissues stem cells, and, if selection is present, the size and growth rate of the largest selected clone. We benchmark SCIFER with published data and then probe bone marrow of 22 non-leukemic individuals for clonal hematopoiesis (CH), identifying CH with known and unknown driver events. Unexpectedly, we find accelerated division of all stem cells in CH, compared to age-matched non-CH individuals, suggesting that the bone marrow environment alters stem cell dynamics in individuals with CH. SCIFER is broadly applicable to renewing somatic tissues to detect and quantify selection.

cancer biology↗

bioRxiv2019

Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay

The megakaryocyte/erythroid Transient Myeloproliferative Disorder (TMD) in newborns with Down Syndrome (DS) occurs when N-terminal truncating mutations of the hemopoietic transcription factor GATA1, that produce GATA1short protein (GATA1s), are acquired early in development. Prior work has shown that murine GATA1s, by itself, causes a transient yolk sac myeloproliferative disorder. However, it is unclear where in the hemopoietic cellular hierarchy GATA1s exerts its effects to produce this myeloproliferative state. Here, through a detailed examination of hemopoiesis from murine GATA1s ES cells and GATA1s embryos we define defects in erythroid and megakaryocytic differentiation that occur relatively in hemopoiesis. GATA1s causes an arrest late in erythroid differentiation in vivo, and even more profoundly in ES-cell derived cultures, with a marked reduction of Ter-119 cells and reduced erythroid gene expression. In megakaryopoiesis, GATA1s causes a differentiation delay at a specific stage, with accumulation of immature, kit-expressing CD41hi megakaryocytic cells. In this specific megakaryocytic compartment, there are increased numbers of GATA1s cells in S-phase of cell cycle and reduced number of apoptotic cells compared to GATA1 cells in the same cell compartment. There is also a delay in maturation of these immature GATA1s megakaryocytic lineage cells compared to GATA1 cells at the same stage of differentiation. Finally, even when GATA1s megakaryocytic cells mature, they mature aberrantly with altered megakaryocyte-specific gene expression and activity of the mature megakaryocyte enzyme, acetylcholinesterase. These studies pinpoint the hemopoietic compartment where GATA1s megakaryocyte myeloproliferation occurs, defining where molecular studies should now be focussed to understand the oncogenic action of GATA1s.\n\nScientific CategoryHaematopoiesis and Stem Cells\n\nKey PointsGATA1s-induced stage-specific differentiation delay increases immature megakaryocytes in vivo and in vitro, during development.\n\nDifferentiation delay is associated with increased numbers of cells in S-phase and reduced apoptosis.

cell biology↗