Molecular landscapes of human hematopoietic stem cells in health and leukemia

Vedi, Aditi; Santoro, Antonella; Dunant, Cyrille F.; Dick, John E.; Laurenti, Elisa

doi:10.1111/nyas.12981

Cited by 28 publications

(25 citation statements)

References 80 publications

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“…Despite recent progress (reviewed in Doulatov et al., 2012, Theocharides et al., 2016, Vedi et al., 2016), several aspects of human hematopoiesis have remained controversial (Chen et al., 2014, Doulatov et al., 2010, McCracken et al., 2013, Notta et al., 2016, Park et al., 2008, Tanner et al., 2014, Woolthuis and Park, 2016). …”

Section: Introductionmentioning

confidence: 99%

DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation

et al. 2016

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SummaryHematopoietic stem cells give rise to all blood cells in a differentiation process that involves widespread epigenome remodeling. Here we present genome-wide reference maps of the associated DNA methylation dynamics. We used a meta-epigenomic approach that combines DNA methylation profiles across many small pools of cells and performed single-cell methylome sequencing to assess cell-to-cell heterogeneity. The resulting dataset identified characteristic differences between HSCs derived from fetal liver, cord blood, bone marrow, and peripheral blood. We also observed lineage-specific DNA methylation between myeloid and lymphoid progenitors, characterized immature multi-lymphoid progenitors, and detected progressive DNA methylation differences in maturing megakaryocytes. We linked these patterns to gene expression, histone modifications, and chromatin accessibility, and we used machine learning to derive a model of human hematopoietic differentiation directly from DNA methylation data. Our results contribute to a better understanding of human hematopoietic stem cell differentiation and provide a framework for studying blood-linked diseases.

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Section: Introductionmentioning

confidence: 99%

DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation

et al. 2016

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“…7, 8, 9, 10, 11, 12 Despite this great leap forward in the understanding of the cellular biology of the disease 20 years ago, culture methods able to maintain LSC activity of human primary samples in vitro were only developed recently, eventually enabling relevant cell-based interrogation of the disease. 13 …”

Section: Introductionmentioning

confidence: 99%

A novel approach for the identification of efficient combination therapies in primary human acute myeloid leukemia specimens

Baccelli

Krošl

Boucher

et al. 2017

Blood Cancer Journal

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Appropriate culture methods for the interrogation of primary leukemic samples were hitherto lacking and current assays for compound screening are not adapted for large-scale investigation of synergistic combinations. In this study, we report a novel approach that efficiently distills synthetic lethal interactions between small molecules active on primary human acute myeloid leukemia (AML) specimens. In single-dose experiments and under culture conditions preserving leukemia stem cell activity, our strategy considerably reduces the number of tests needed for the identification of promising compound combinations. Initially conducted with a selected library of 5000 small molecules and 20 primary AML specimens, it reveals 5 broad classes of sensitized therapeutic target pathways along with their synergistic patient-specific fingerprints. This novel method opens new avenues for the development of AML personalized therapeutics and may be generalized to other tumor types, for which in vitro cancer stem cell cultures have been developed.

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“…It is a kind of acquired hematopoietic stem cell malignant clonal disease [1,2]. At present, the priority treatment of leukemia is chemotherapy [3].…”

Section: Introductionmentioning

confidence: 99%

CD33, CD96 and Death Associated Protein Kinase (DAPK) Expression Are Associated with the Survival Rate and/or Response to the Chemotherapy in the Patients with Acute Myeloid Leukemia (AML)

Jiang

Yao

et al. 2017

Med Sci Monit

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BackgroundLeukemia stem cells (LSC) are involved in the incidence, drug resistance, and relapse of leukemia while LSC-related antigen CD33, CD96, and DAPK expression in AML and its prognosis is still unclear. This study explored LSC-related antigens expression in acute myeloid leukemia (AML) and its prognosis.Material/MethodsA total of 156 cases of AML patients were enrolled in the experiment. The expression of CD33, CD96, and DAPK in CD34+CD38−CD123+ LSC were tested by flow cytometry. The survival curve was established using the Kaplan-Meier method.ResultsAmong different subtypes of AML, the positive rate of CD33 was M3> M5> M1> M2> M4; for CD96 it was M5> M4> M2> M3> M1; and for DAPK it was M3> M2> M5> M4> M1. After chemotherapy, the response rate in CD33 and CD96 high expression groups, and DAPK low expression group was significantly lower than the groups with CD33 low expression, CD96 low expression, and DAPK high expression. The median survival time in the CD33 high expression group was markedly lower than the CD33 low expression group (36.5 months). The CD96 high expression group exhibited obviously shorter median survival time than the CD96 low expression group. The DAPK high expression group exhibited longer median survival time than the DAPK low expression group.ConclusionsCD33 and CD96 overexpression, and DAPK downregulation in the LSC of AML patients were associated with poor chemotherapy effect and prognosis, and higher recurrence rate.

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Molecular landscapes of human hematopoietic stem cells in health and leukemia

Cited by 28 publications

References 80 publications

DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation

DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation

A novel approach for the identification of efficient combination therapies in primary human acute myeloid leukemia specimens

CD33, CD96 and Death Associated Protein Kinase (DAPK) Expression Are Associated with the Survival Rate and/or Response to the Chemotherapy in the Patients with Acute Myeloid Leukemia (AML)

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