Chronic myelomonocytic leukaemia stem cell transcriptomes anticipate disease morphology and outcomeCitation formats

  • External authors:
  • Arundhati Dongre
  • Kristian Gurashi
  • Joanna Storer

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Chronic myelomonocytic leukaemia stem cell transcriptomes anticipate disease morphology and outcome. / Wiseman, Daniel; Baker, Syed Murtuza; Dongre, Arundhati; Gurashi, Kristian; Storer, Joanna; Somervaille, Tim; Batta, Kiran.

In: EBioMedicine, Vol. 58, 102904, 04.08.2020.

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@article{58d319773b184e579b0a6516aed73885,
title = "Chronic myelomonocytic leukaemia stem cell transcriptomes anticipate disease morphology and outcome",
abstract = "Background: Chronic myelomonocytic leukaemia (CMML) is a clinically heterogeneous stem cell malignancy with overlapping features of myelodysplasia and myeloproliferation. Over 90% of patients carry mutations in epigenetic and/or splicing genes, typically detectable in the LinCD34+CD38- immunophenotypic stem cell compartment in which the leukaemia-initiating cells reside. Transcriptional dysregulation at the stem cell level is likely fundamental to disease onset and progression. Methods: We performed single-cell RNA sequencing on 6826 Lin-CD34+CD38- stem cells from CMML patients and healthy controls using the droplet-based, ultra-high-throughput 10x platform.Findings: We found substantial inter- and intra-patient heterogeneity, with CMML stem cells displaying distinctive transcriptional programs. Compared with normal controls, CMML stem cells exhibited transcriptomes characterized by increased expression of myeloid-lineage and cell cycle genes, and lower expression of genes selectively expressed by normal haematopoietic stem cells. Neutrophil-primed progenitor genes and a MYC transcription factor regulome were prominent in stem cells from CMML-1 patients, whereas CMML-2 stem cells exhibited strong expression of interferon-regulatory factor regulomes, including those associated with IRF1, IRF7 and IRF8. CMML-1 and CMML-2 stem cells (stages distinguished by proportion of downstream blasts and promonocytes) differed substantially in both transcriptome and pseudotime, indicating fundamentally different biology underpinning these disease states. Gene expression and pathway analyses highlighted potentially tractable therapeutic vulnerabilities for downstream investigation. Importantly, CMML patients harboured variably-sized subpopulations of transcriptionally normal stem cells, indicating a potential reservoir to restore functional haematopoiesis.Interpretation: Our findings provide novel insights into the CMML stem cell compartment, revealing an unexpected degree of heterogeneity and demonstrating that CMML stem cell transcriptomes anticipate disease morphology, and therefore outcome. ",
keywords = "CMML, Leukaemia, Stem cells, sc-RNA Seq",
author = "Daniel Wiseman and Baker, {Syed Murtuza} and Arundhati Dongre and Kristian Gurashi and Joanna Storer and Tim Somervaille and Kiran Batta",
year = "2020",
month = aug,
day = "4",
doi = "10.1016/j.ebiom.2020.102904",
language = "English",
volume = "58",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

RIS

TY - JOUR

T1 - Chronic myelomonocytic leukaemia stem cell transcriptomes anticipate disease morphology and outcome

AU - Wiseman, Daniel

AU - Baker, Syed Murtuza

AU - Dongre, Arundhati

AU - Gurashi, Kristian

AU - Storer, Joanna

AU - Somervaille, Tim

AU - Batta, Kiran

PY - 2020/8/4

Y1 - 2020/8/4

N2 - Background: Chronic myelomonocytic leukaemia (CMML) is a clinically heterogeneous stem cell malignancy with overlapping features of myelodysplasia and myeloproliferation. Over 90% of patients carry mutations in epigenetic and/or splicing genes, typically detectable in the LinCD34+CD38- immunophenotypic stem cell compartment in which the leukaemia-initiating cells reside. Transcriptional dysregulation at the stem cell level is likely fundamental to disease onset and progression. Methods: We performed single-cell RNA sequencing on 6826 Lin-CD34+CD38- stem cells from CMML patients and healthy controls using the droplet-based, ultra-high-throughput 10x platform.Findings: We found substantial inter- and intra-patient heterogeneity, with CMML stem cells displaying distinctive transcriptional programs. Compared with normal controls, CMML stem cells exhibited transcriptomes characterized by increased expression of myeloid-lineage and cell cycle genes, and lower expression of genes selectively expressed by normal haematopoietic stem cells. Neutrophil-primed progenitor genes and a MYC transcription factor regulome were prominent in stem cells from CMML-1 patients, whereas CMML-2 stem cells exhibited strong expression of interferon-regulatory factor regulomes, including those associated with IRF1, IRF7 and IRF8. CMML-1 and CMML-2 stem cells (stages distinguished by proportion of downstream blasts and promonocytes) differed substantially in both transcriptome and pseudotime, indicating fundamentally different biology underpinning these disease states. Gene expression and pathway analyses highlighted potentially tractable therapeutic vulnerabilities for downstream investigation. Importantly, CMML patients harboured variably-sized subpopulations of transcriptionally normal stem cells, indicating a potential reservoir to restore functional haematopoiesis.Interpretation: Our findings provide novel insights into the CMML stem cell compartment, revealing an unexpected degree of heterogeneity and demonstrating that CMML stem cell transcriptomes anticipate disease morphology, and therefore outcome.

AB - Background: Chronic myelomonocytic leukaemia (CMML) is a clinically heterogeneous stem cell malignancy with overlapping features of myelodysplasia and myeloproliferation. Over 90% of patients carry mutations in epigenetic and/or splicing genes, typically detectable in the LinCD34+CD38- immunophenotypic stem cell compartment in which the leukaemia-initiating cells reside. Transcriptional dysregulation at the stem cell level is likely fundamental to disease onset and progression. Methods: We performed single-cell RNA sequencing on 6826 Lin-CD34+CD38- stem cells from CMML patients and healthy controls using the droplet-based, ultra-high-throughput 10x platform.Findings: We found substantial inter- and intra-patient heterogeneity, with CMML stem cells displaying distinctive transcriptional programs. Compared with normal controls, CMML stem cells exhibited transcriptomes characterized by increased expression of myeloid-lineage and cell cycle genes, and lower expression of genes selectively expressed by normal haematopoietic stem cells. Neutrophil-primed progenitor genes and a MYC transcription factor regulome were prominent in stem cells from CMML-1 patients, whereas CMML-2 stem cells exhibited strong expression of interferon-regulatory factor regulomes, including those associated with IRF1, IRF7 and IRF8. CMML-1 and CMML-2 stem cells (stages distinguished by proportion of downstream blasts and promonocytes) differed substantially in both transcriptome and pseudotime, indicating fundamentally different biology underpinning these disease states. Gene expression and pathway analyses highlighted potentially tractable therapeutic vulnerabilities for downstream investigation. Importantly, CMML patients harboured variably-sized subpopulations of transcriptionally normal stem cells, indicating a potential reservoir to restore functional haematopoiesis.Interpretation: Our findings provide novel insights into the CMML stem cell compartment, revealing an unexpected degree of heterogeneity and demonstrating that CMML stem cell transcriptomes anticipate disease morphology, and therefore outcome.

KW - CMML

KW - Leukaemia

KW - Stem cells

KW - sc-RNA Seq

U2 - 10.1016/j.ebiom.2020.102904

DO - 10.1016/j.ebiom.2020.102904

M3 - Article

C2 - 32763828

VL - 58

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

M1 - 102904

ER -