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Critical modulation of hematopoietic lineage fate by the PAR/bZIP transcription factor Hepatic Leukemia Factor

ABSTRACT: Blood cell formation is a tightly regulated process initiated from a rare population of multipotent hematopoietic stem cells. Subsequent differentiation proceeds in a hierarchical manner with the generation of intermediate progenitor cells, in which alternative lineage potentials become gradually restricted. A deeper understanding of these events is crucial not only to understand normal blood cell formation, but also for leukemia, where a defining feature is inappropriate differentiation. Here, we identified Hepatic Leukemia Factor (Hlf) as being highly and selectively expressed in primitive multipotent hematopoietic stem and progenitors. We demonstrate that Hlf is a strong negative regulator of B-, NK- and T cell development and instructs multipotent progenitors to adopt a myeloid fate in a cell autonomous manner; phenotypes underwritten by the induction of myeloid affiliated transcriptional programs, the concomitant ablation of lymphoid gene programs and genome-wide binding spectra that involved active enhancers of myeloid-competent cells. Collectively, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE69817 | GEO | 2016/07/11

SECONDARY ACCESSION(S): PRJNA286862

REPOSITORIES: GEO

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Critical modulation of hematopoietic lineage fate by the PAR/bZIP transcription factor Hepatic Leukemia Factor

Project description:Blood cell formation is a tightly regulated process initiated from a rare population of multipotent hematopoietic stem cells. Subsequent differentiation proceeds in a hierarchical manner with the generation of intermediate progenitor cells, in which alternative lineage potentials become gradually restricted. A deeper understanding of these events is crucial not only to understand normal blood cell formation, but also for leukemia, where a defining feature is inappropriate differentiation. Here, we identified Hepatic Leukemia Factor (Hlf) as being highly and selectively expressed in primitive multipotent hematopoietic stem and progenitors. We demonstrate that Hlf is a strong negative regulator of B-, NK- and T cell development and instructs multipotent progenitors to adopt a myeloid fate in a cell autonomous manner; phenotypes underwritten by the induction of myeloid affiliated transcriptional programs, the concomitant ablation of lymphoid gene programs and a genome-wide binding spectra that involved active enhancers of myeloid-competent cells. Collectively, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis. Gene expression profiling of control or Hlf/Hlf lentivirus infected GMLPs (2 replicates per group) and Hlf inducible GMLPs maintained for 4 days on OP9 stroma in the presence or absence of doxycycline (2 replicates per group)

2016-06-12 | E-GEOD-69858 | biostudies-arrayexpress

Critical modulation of hematopoietic lineage fate by Hepatic Leukemia Factor

Project description:A gradual restriction in lineage potential of multipotent stem/progenitor cells is a hallmark of adult hematopoiesis, but the underlying molecular events governing these processes remain incompletely understood. Here, we identified robust expression of the leukemia-associated transcription factor Hepatic Leukemia Factor (Hlf) in normal multipotent hematopoietic progenitors, which was rapidly downregulated upon differentiation. Interference with its’ normal downregulation revealed Hlf as a strong negative regulator of lymphoid development, while remaining compatible with myeloid fates. Reciprocally, we observed rapid lymphoid commitment upon reduced Hlf activity. The arising phenotypes resulted from Hlf-binding to active enhancers of myeloid-competent cells, transcriptional induction of myeloid and ablation of lymphoid gene programs, with Hlf induction of Nuclear Factor I C (Nfic) as a functionally relevant target gene. Thereby, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis.

2016-06-12 | GSE69858 | GEO

Critical modulation of hematopoietic lineage fate by Hepatic Leukemia Factor

Project description:Hematopoiesis commences with a gradual restriction in lineage potential of multipotent stem/progenitor cells, but the underlying molecular events of this remain incompletely understood. We here identify robust expression of the transcription factor Hepatic Leukemia Factor (Hlf) in multipotent hematopoietic progenitors, which is rapidly lost with differentiation. Prolonged Hlf expression reveals it as a strong negative regulator of lymphoid development and results in a pronounced and reversible differentiation block in the B-cell lineage, while remaining compatible with myeloid fates. Reciprocally, we observe rapid lymphoid commitment upon eduction of Hlf activity. These phenotypes result from Hlf-binding to active enhancers of myeloid-competent cells, induction of myeloid-affiliated transcription and ablation of lymphoid gene programs, with Hlf induction of Nuclear Factor I C (Nfic) as a functionally relevant target gene. Collectively, we establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage restricted progeny.

2018-10-30 | GSE106555 | GEO

Quantitative proteomics of Hematopoietic Stem Cells during acute inflammation

Project description:Infections are associated with extensive consumption of blood platelets representing a high risk for health. How the hematopoietic system coordinates the rapid and efficient regeneration of this particular lineage during such stress scenarios remains unclear. Here we report that the phenotypic hematopoietic stem cell (HSC) compartment contains highly potent megakaryocyte-committed progenitors (hipMkPs), a cell population that shares many features with multipotent HSCs and serves as a lineage-restricted emergency pool for inflammatory insults. Our data show that during homeostasis, hipMkPs are maintained in a primed but quiescent state, thus contributing little to steady-state megakaryopoiesis. Moreover, homeostatic hipMkPs show expression of megakaryocyte lineage priming transcripts for which protein synthesis is suppressed. We demonstrate that acute inflammatory signaling instructs activation of hipMkPs, as well as Mk protein production from pre-existing transcripts and drives a rapid maturation of hipMkPs and other Mk progenitors. This results in an efficient regeneration of platelets that are lost during inflammatory insult. Thus, our study reveals an elegant emergency machinery that counteracts life-threating depletions in the platelet pool during acute inflammation.

2015-08-26 | PXD001500 | Pride

Transcriptome analysis of nascent hematopoietic cells

Project description:During ontogeny, hematopoietic stem cells (HSCs) and erythroid-myeloid progenitors (EMPs) are generated from distinct hemogenic endothelium. Nascent HSCs and EMPs are distinguished by the expression of Hlf. To obtain mechanistic insight into HSC specification, we compared the gene expression profiles between Hlf+ and Hlf- nascent hematopoietic cells.

2019-05-03 | GSE114164 | GEO

Expression data from Myc/Bcl2-transformed primary mouse leukemia cells

Project description:Unfavorable patient survival coincides with the lineage plasticity observed in ~20% of human acute leukemias. These cases are assumed to arise from hematopoietic stem cells, which have stable multipotent differentiation potential. However, here we report that plasticity in leukemia can result from instable lineage identity states inherited from differentiating progenitor cells. Using mice with enhanced c-Myc/Bcl2-expression, we show that T-lymphoid progenitors retain broad malignant lineage switching potential with a high capacity to differentiate into myeloid leukemia.

2016-09-01 | GSE80739 | GEO

Hematopoietic differentiation is required for initiation of acute myeloid leukemia [ATAC-seq]

Project description:Leukemia initiating cells (LICs) of acute myeloid leukemia (AML) may arise from self-renewing hematopoietic stem cells (HSCs) and from committed progenitors. However, it remains unclear how leukemia-associated oncogenes instruct LIC formation from cells of different origins and if differentiation along the normal hematopoietic hierarchy is involved. Here, using murine models with the driver mutations MLL-AF9 or MOZ-TIF2, we found that regardless of the transformed cell types, myelomonocytic differentiation to the granulocyte macrophage progenitor (GMP) stage is critical for LIC generation. Blocking myeloid differentiation through disrupting the lineage-restricted transcription factor C/EBPa eliminates GMPs, blocks normal granulopoiesis, and prevents AML development. In contrast, restoring myeloid differentiation through inflammatory cytokines “rescues” AML transformation. Our findings identify myeloid differentiation as a critical step in LIC formation and AML development, thus guiding new therapeutic approaches. Examination of chromatin accessibility in Cebpa knock-out and control conditions.

2015-08-04 | E-GEOD-71688 | biostudies-arrayexpress

miR-125a Confers Multi-Lineage Long-Term Repopulating Stem Cell Activity to Murine and Human Hematopoietic Progenitors

Project description:Umbilical cord blood (CB) is a non-invasive, convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. One feasible option would be to expand HSCs to improve therapeutic outcome, however available protocols and the molecular mechanisms governing the self-renewal of HSC are unclear. Here we show that ectopic expression of a single miRNA, miR-125a, in purified murine and human multipotent progenitors (MPP) resulted in increased self-renewal and robust long-term multi-lineage repopulation in transplanted recipient mice. Using quantitative proteomics and Western blot analysis, we identified a restricted set of miR-125a targets which revealed the involvement of the MAP kinase signaling pathway in conferring long-term repopulating capacity to multipotent progenitors in human and mice. Our findings offer the innovative potential to use MPP with enhanced self-renewal activity to augment limited sources of HSC to improve clinical protocols.

2017-01-11 | PXD003931 | Pride

Transcriptional landscape, long non-coding RNAs and post-transcriptional regulation in hematopoietic stem/progenitor cell differentiation

Project description:Hematopoietic stem cells (HSC) possess life-long self-renewal activity and generate a series of multipotent progenitors that differentiate into lineage-committed progenitors and subsequently mature cells. Recently, functionally distinct stem and progenitor cell types have been identified, however, a systems-wide understanding of the underlying gene regulation is lacking. Here, we present the global transcriptome of ex vivo isolated mouse multipotent hematopoietic stem/progenitor cells (HSPCs, LinnegSca-1+c-Kit+) and myeloid committed precursors (LinnegSca-1-c-Kit+) as revealed by next-generation sequencing (RNA-seq).

2014-10-08 | E-MTAB-1963 | biostudies-arrayexpress

Nucleoporin Nup358 drives the differentiation of myeloid-biased multipotent progenitors by modulating HDAC3 nuclear translocation

Project description:We report that Nup358, a nucleoporin linked to acute myeloid leukemia and myeloproliferative neoplasms, is required for the developmental progression of early myeloid progenitors. We found that loss of Nup358 in mice is associated with the accumulation of myeloid-primed multipotent progenitors (MPPs) in bone marrow and the loss of myeloid-committed progenitors and mature myeloid cells. Accumulated MPPs in Nup358 knockout mice are greatly restricted to megakaryocyte/erythrocyte biased MPP2 cells and fail to progress into committed myeloid progenitors.

2024-04-11 | GSE208436 | GEO

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