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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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B-myb is Essential Regulator of Hematopoietic Stem Cell and Myeloid Progenitor Cell Development

ABSTRACT: The B-myb (MYBL2) gene is a member of the MYB family of transcription factors and is involved in cell cycle regulation, DNA replication and maintenance of genomic integrity. However, its function during adult development and hematopoiesis is unknown. We show here that conditional inactivation of B-myb in vivo results in depletion of the HSC pool, leading to profound reductions in mature lymphoid, erythroid and myeloid cells. This defect is autonomous to the bone marrow and is first evident in the HSCs, which accumulate in the S and G2/M phases. B-myb inactivation also causes defects in the myeloid progenitor compartment and results in an accumulation of GMPs. Microarray studies indicate that B-myb null LKS+ cells differentially express genes that direct myeloid lineage development and commitment, suggesting that B-myb is a key player in controlling cell fate. Collectively, these studies demonstrate that B-myb is essential for HSC and progenitor maintenance and survival during hematopoiesis. Total RNA was isolated from FACS purified LKS+ cells isolated from pIpC-treated control and B-myb floxed-MxCre mice. Each sample is derived from a pool of 3-5 mice. 2 samples were analyzed for each genotype.

ORGANISM(S): Mus musculus

SUBMITTER: Stacey Baker

PROVIDER: E-GEOD-53875 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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B-myb is Essential Regulator of Hematopoietic Stem Cell and Myeloid Progenitor Cell Development

Project description:The B-myb (MYBL2) gene is a member of the MYB family of transcription factors and is involved in cell cycle regulation, DNA replication and maintenance of genomic integrity. However, its function during adult development and hematopoiesis is unknown. We show here that conditional inactivation of B-myb in vivo results in depletion of the HSC pool, leading to profound reductions in mature lymphoid, erythroid and myeloid cells. This defect is autonomous to the bone marrow and is first evident in the HSCs, which accumulate in the S and G2/M phases. B-myb inactivation also causes defects in the myeloid progenitor compartment and results in an accumulation of GMPs. Microarray studies indicate that B-myb null LKS+ cells differentially express genes that direct myeloid lineage development and commitment, suggesting that B-myb is a key player in controlling cell fate. Collectively, these studies demonstrate that B-myb is essential for HSC and progenitor maintenance and survival during hematopoiesis. Total RNA was isolated from FACS purified LKS+ cells isolated from pIpC-treated control and B-myb floxed-MxCre mice.

2014-02-12 | GSE53875 | GEO

scRNAseq for bone marrow cells from Cebpαcre/+ R26EYFP/+ SbdsF/F (neutropenia) mice vs Cebpαcre/+ R26EYFP/+ Sbds+/+ (Ctrl) mice

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The Apcmin mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS

Project description:Apc, a negative regulator of the canonical Wnt signaling pathway, is a bona-fide tumor suppressor whose loss of function results in intestinal polyposis. APC is located in a commonly deleted region on human chromosome 5q, associated with myelodysplastic syndrome (MDS) suggesting that haploinsufficiency of APC contributes to the MDS phenotype. Analysis of the hematopoietic system of mice with the Apcmin allele that results in a premature stop codon and loss of function, showed no abnormality in steady state hematopoiesis. Bone marrow derived from Apcmin mice showed enhanced repopulation potential, indicating of a cell intrinsic gain of function in the long-term hematopoietic stem cell (HSC) population. However, Apcmin bone marrow was unable to repopulate secondary recipients due to loss of the quiescent HSC population. Apcmin mice developed a myelodysplastic/ myeloproliferative phenotype. Our data indicate that Wnt activation through haploinsufficiency of Apc causes insidious loss of HSC function that is only evident in serial transplantation strategies. These data provide a cautionary note for HSC expansion strategies through Wnt pathway activation, provide evidence that cell extrinsic factors can contribute to the development of myeloid disease and indicate that loss of function of APC may contribute to the phenotype observed in patients with MDS and del(5q). LKS+ cells were isolated from Apcmin or WT mice using high-speed multiparameter flow cytometry. At least 2x104 cells per mouse were isolated with confirmed purity in excess of 90%. The cells were treated with RLT lysis buffer (Qiagen) containing beta-mercaptoethanol to stabilize RNA. RNA was extracted using Qiagen RNeasy Micro Kit according to manufacturers instruction. The RNA was amplified using a linear amplification protocol (Nugen Ovation V2 amplification system). cDNA was fragmented and biotinylated before hybridization onto Affymetrix mouse genome 430 2.0 Array chips

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2010-05-28 | E-GEOD-21842 | biostudies-arrayexpress

Transcription profiling of mouse gain- and loss-of-function Hedgehod (Hh) genetic models reveals Hedgehog signaling is dispensable for adult hematopoietic stem cell function

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MYB is an essential regulator of primitive human hematopoiesis in human pluripotent stem cell differentiation cultures.

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2021-01-31 | GSE125761 | GEO

Hedgehog signaling is dispensable for adult hematopoietic stem cell function

Project description:The Hedgehog (Hh) signaling pathway is a developmentally conserved regulator of stem cell function. Several reports suggested that Hh signaling is an important regulator of hematopoietic stem cell (HSC) maintenance and differentiation. Here we test this hypothesis in vivo using both gain- and loss-of-function Hh genetic models. Surprisingly, our studies demonstrate that conditional Smoothened (Smo) deletion or over-activation has no significant effects on adult HSC self-renewal and function. Moreover, they indicate a lack of synergism between the Notch and Hh pathways in HSC function, as RBPJ- and Smo-deficiency do not affect hematopoiesis. In agreement with this notion, detailed genome-wide transcriptome analysis reveals that silencing of Hh signaling does not significantly alter the HSC-specific gene expression “signature”. Our studies demonstrate that the Hh signaling pathway is dispensable for adult HSC function and suggest that the Hh pathway can be targeted in future clinical trials addressing the effect of Hh inhibition on leukemia-initiating cell maintenance. Transcriptional consequences of inactivating Smo (hh loss-of-function) in LKS cells.

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Expression data from side population subfraction hematopoietic stem cells

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