The journey of neutropoiesis: how complex landscapes in bone marrow guide continuous neutrophil lineage determination

Neutrophils are the most abundant white blood cell, and differentiate in homeostasis in the bone marrow from hematopoietic stem cells (HSCs) via multiple intermediate progenitor cells into mature cells that enter the circulation. Recent findings support a continuous model of differentiation in the bone marrow of heterogeneous HSCs and progenitor populations. Cell fate decisions both at the level of proliferation and differentiation are enforced through expression of lineage-determining transcription factors (LDTFs) and their interactions, that are influenced by both intrinsic (intracellular) as well as extrinsic (extracellular) mechanisms. Neutrophil homeostasis is subjected to positive feedback loops, stemming from the gut microbiome, as well as negative feedback loops resulting from the clearance of apoptotic neutrophils by mature macrophages. Finally, the cellular kinetics regarding the replenishing of the mature neutrophil pool is discussed in light of recent, contradictory data.

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Notch Signaling Induces Megakaryocytic Cell Fate.

Blood ◽

10.1182/blood.v110.11.200.200 ◽

2007 ◽

Vol 110 (11) ◽

pp. 200-200

Author(s):

Thomas Mercher ◽

Melanie Cornejo ◽

Christopher Sears ◽

Thomas Kindler ◽

Sandra Moore ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Notch Signaling ◽

Cell Fate ◽

Marrow Transplantation ◽

Notch Pathway ◽

Severe Thrombocytopenia ◽

Hematopoietic Stem ◽

Cell Fate Decisions

Abstract The Notch pathway regulates a broad range of biological mechanisms including proliferation, border formation and cell fate decisions. In the hematopoietic system, Notch signaling is generally thought to specify T cell lineage fate at the expense of the B cell whereas its role in the myeloid lineage development is unclear. When using heterotypic co-cultures of murine primary hematopoietic stem cells (HSC: Lin-Sca1+Kit+) with OP9 stromal cells, or OP9 cells expressing the Notch ligand Delta1 (OP9-DL1), we unexpectedly observed the development of large cells with cytoplasmic protrusions reminiscent of proplatelet production by megakaryocytes on OP9-DL1 stroma. These cells stained positive for acetylcholinesterase, specific for megakaryocyte, and displayed large polylobated nuclei. Flow cytometric analysis indicated a 10-fold increase in the number of CD41+ cells in OP9-DL1 co-cultures compared to parental OP9 co-cultures. Expression of a constitutively active intra-cellular Notch (ICN) mutant allowed differentiation of HSC into CD41+ cells in parental OP9 co-cultures without DL1 stimulation, whereas expression of a dominant-negative MAML1 (dnMAML1) mutant abrogated this effect in OP9-DL1 co-cultures. In addition, megakaryocyte differentiation in OP9-DL1 co-cultures was blocked by γ-secretase inhibitors treatment and rescued by ectopic expression of ICN. Global gene expression analysis demonstrated engagement of a megakaryopoietic transcriptional program when HSC were co-cultured with OP9-DL1 vs. OP9 stroma or OP9-DL1 stroma treated with γ-secretase inhibitor. Bone marrow transplantation experiments with ICN, resulted in enhanced megakaryopoiesis in vivo with increased MEP numbers and megakaryocyte colony formation. Furthermore, transplantation of bone marrow cells transduced with dnMAML1 significantly impaired megakaryopoiesis in vivo with a 4- to 7-fold decrease in maturing megakaryocytes. These findings demonstrate a positive regulatory role for Notch signaling in specification of megakaryocyte development, and indicate that Notch plays a complex role in cell fate decisions among myeloid progenitors. They suggest the possibility that inhibition of Notch signaling may have therapeutic potential in malignancies of the megakaryocytic lineage. Furthermore, Notch pathway stimulation could be of value in enhancing megakaryocyte growth in clinical contexts associated with severe thrombocytopenia, such as hematopoietic reconstitution following bone marrow transplantation or chemotherapy.

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Down-Regulation of Homeobox Gene Ventx Promotes Expansion of Human Bone Marrow Hematopoietic Stem Cells (HSC)

Blood ◽

10.1182/blood.v118.21.1272.1272 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1272-1272

Author(s):

Hong (Jenny) Gao ◽

Xiaoming Wu ◽

Yan Sun ◽

Jiayun Lu ◽

Leslie E Silberstein ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Cell Fate ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Great Promise ◽

Down Regulation ◽

Hematopoietic Stem ◽

Proliferation And Differentiation

Abstract Abstract 1272 Hematopoietic stem cells (HSC) give rise to mature cells of all lineages of blood and immune systems. HSC transplantation has shown great promise in the treatment of malignancies, reconstitution of hematopoietic systems and HSC-based gene therapy. Cell intrinsic factors/pathways have been the targets of intensive investigation for its potential application in HSC expansion. Over the past decades, several critical cell fate determination pathways, such as the Wnt signaling pathways and senescence pathways have been implicated in the proliferation and differentiation of HSC. Moreover, overexpression of HoxB4 and BMI1 was found to be able to expand human HSC 2∼3 folds. Nevertheless, the regulatory mechanisms of HSC proliferation and differentiation remain incompletely understood and safe and efficacious expansion of human HSC remains as a fundamental challenge that limits the clinical application of HSC-based therapy. VentX is a human homologue of the Xenopus homeobox protein Xom of the BMP4 signaling pathway. Using Xenopus model and methods of reverse genetics, our recent work showed that VentX is a LEF/TCF associated Wnt repressor and an activator of senescence pathways. VentX expression is highly regulated and restricted in hematopoietic cells and serves a major regulator of hematopoietic cell differentiation. To explore the potential role of VentX in proliferation and differentiation of HSC during hematopoiesis, we quantified VentX expression during hematopoiesis, using qRT-PCR methods and examined the effects of altered VentX expression on HSC properties in vitro and in vivo. Our data showed that VentX expression is significantly up-regulated during oncogenesis of hematopioetic cells. We demonstrated that lentiviral knockdown of VentX allowed for more than 5 fold ex vivo expansion of human HSC with balanced lineage development. Importantly, transient knockdown of VentX by siRNA also led to expansion of HSC. The effect of VentX down-regulation on the expansion of human HSC was also demonstrated by enhanced engraftment in the SCID/NODγ2null mouse model. Consistent with its role as a novel regulator of HSC, overexpression of VentX significantly inhibited clonal genesis of HSC. Mechanistically, we demonstrated that VentX controls the expression of cell cycle regulators downstream of the Wnt and senescence pathways, such as the C-myc, CyclinD1 and p21. In summary, using methods of reverse genetic and developmental modeling, we identified VentX as a novel regulator for expansion of human BM HSC. The results of our investigations provide novel insight in regulating HSC proliferation and differentiation. In addition, the findings that transient down-regulation of VentX by SiRNA lead to efficient expansion of bone marrow HSC suggests that VentX may serve as a novel target for safe expansion of HSC for its potential clinical applications. Disclosures: No relevant conflicts of interest to declare.

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Regulation of Hematopoietic Stem and Progenitor Cell Differentiation By Mirn23a/b Micrornas

Blood ◽

10.1182/blood.v128.22.3880.3880 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3880-3880

Author(s):

Jeffrey Kurkewich ◽

Justin Hansen ◽

Nathan Klopfenstein ◽

Helen Zhang ◽

Christian Wood ◽

...

Keyword(s):

Bone Marrow ◽

Transcription Factors ◽

Cell Fate ◽

Negative Regulation ◽

Mirna Cluster ◽

Hematopoietic Stem ◽

Smad Pathway ◽

Cell Fate Decisions ◽

Regulatory Feedback Loop ◽

Marrow Cellularity

Abstract Differentiation from hematopoietic stem and progenitor cells (HSPCs) to committed blood lineages is dependent on lineage specific transcription factors that simultaneously promote gene expression that commits progenitors to specific lineages while repressing genes associated with alternative lineages. In addition to transcription factors, small non-coding microRNAs (miRNAs) also have the potential to influence cell fate decisions through negative regulation of lineage specific genes. We previously observed that germline knockout of the mirn23a miRNA cluster (which codes for mature miRNAs miR-23a, miR-27a, and miR-24-2) resulted in increased common lymphoid progenitors (CLPs) and B cells with a concomitant decrease in granulocyte/monocyte progenitors (GMPs) and their progeny. This was the first evidence of a miRNA being able to influence a lymphoid/myeloid cell fate decision using a genetic knockout model. To follow up these results, we sought to identify a detailed molecular mechanism of the mirn23a-/- mouse phenotype. Evaluation of HSPC populations by flow cytometry revealed that while mirn23a-/- mice have no difference s in their LT-HSC populations, they show imbalanced levels of MPP3 and MPP4 populations, suggesting that bifurcation from the MPP2 to the MPP3/MPP4 is the earliest cell type regulated by mirn23a to influence hematopoietic cell fate decisions. RNA and protein analysis of multipotent EML cell lines generated from wildtype and mirn23a-/- mice revealed that mirn23a negatively regulated critical HSPC genes Runx1, Satb1, Ikzf1, Mef2c, Bach1, and Bach2 that are involved in committing MPPs to CLPs. Additionally, genes associated with the commitment of CLPs to B cells, EBF1 and Pax5, were also increased. We observed that miR-24-2 target, Trib3, antagonizes PI3K/AKT signaling to promote EBF1 and Pax5 expression through nuclear accumulation of FoxO1. Trib3 also agonizes the BMP/Smad pathway through negative regulation of E3-ubiquitinase Smurf1. Ex vivo OP9 cultures with primary mirn23a-/- cells cultured with FoxO1 and BMP inhibitors revealed that both the PI3K/Akt and BMP/Smad pathway are critical for mirn23a-/- phenotypes. Consistent with mirn23a being a critical gene for myeloid commitment of hematopoietic progenitors, we observe that B Cell factor EBF1 represses transcription of mirn23a, creating a regulatory feedback loop between mirn23a and EBF1. In addition to mirn23a, there is a homologous mirn23b miRNA cluster that is expressed at lower levels in hematopoietic cells. To investigate compound loss of mirn23a and mirn23b in adult hematopoiesis, we generated mirn23a-/-mirn23bf/f Mx-1 cre mice to circumvent variable embryonic/ neonatal lethality. These mice showed a further increase in B lymphopoiesis and decrease in myelopoiesis compared to mirn23a-/- mice. Interestingly, these mice also exhibited decreased bone marrow cellularity at 3 weeks post mirn23b excision. As judged by overall numbers and percent of bone marrow, LT-HSC, MPP, and LSK populations were decreased. We are currently investigating the underlying mechanism for the decreased stem cells and overall cellularity. Overall, these results show that mirn23a/b miRNAs bias cell fate decisions at the MPP through negative regulation of critical lymphoid transcription factors. Sustained commitment to the B cell lineage is dependent on both the PI3K/Akt and BMP/Smad signaling pathways, both of which are regulated by mirn23a target Trib3. In turn, EBF1 negatively regulates mirn23a, creating a regulatory feedback loop between EBF1 and mirn23a. Compound loss of mirn23a/mirn23b results in decreased bone marrow cellularity and stem cell loss. Disclosures No relevant conflicts of interest to declare.

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Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells

Blood ◽

10.1182/blood-2003-07-2254 ◽

2004 ◽

Vol 103 (9) ◽

pp. 3511-3515 ◽

Cited By ~ 150

Author(s):

Franziska Jundt ◽

Kristina Schulze Pröbsting ◽

Ioannis Anagnostopoulos ◽

Gwendolin Muehlinghaus ◽

Manik Chatterjee ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Notch Signaling ◽

Cell Fate ◽

Plasma Cells ◽

Control Cell ◽

Hematopoietic Stem ◽

Cell Fate Decisions ◽

Notch Receptors

Abstract Notch receptors expressed on hematopoietic stem cells interact with their ligands on bone marrow stromal cells and thereby control cell fate decisions and survival. We recently demonstrated that Notch signaling is involved in proliferation and survival of B cell-derived tumor cells of classic Hodgkin disease and described a novel mechanism for the oncogenic capacity of Notch. In this study we investigated whether Notch signaling is involved in the tight interactions between neoplastic plasma cells and their bone marrow microenvironment, which are essential for tumor cell growth in multiple myeloma (MM). Here we demonstrate that Notch receptors and their ligand Jagged1 are highly expressed in cultured and primary MM cells, whereas nonneoplastic counterparts show low to undetectable levels of Notch. Functional data indicate that ligand-induced Notch signaling is a growth factor for MM cells and suggest that these interactions contribute to myelomagenesis in vivo. (Blood. 2004;103:3511-3515)

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The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

International Journal of Molecular Sciences ◽

10.3390/ijms22136857 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6857

Author(s):

Samantha Bruno ◽

Manuela Mancini ◽

Sara De Santis ◽

Cecilia Monaldi ◽

Michele Cavo ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Cell Fate ◽

Myeloid Leukemia ◽

Hematologic Malignancy ◽

Bone Marrow Microenvironment ◽

Metabolic Adaptation ◽

Cell Fate Decisions ◽

Wide Range ◽

Acute Myeloid

Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.

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The effects of locomotion on bone marrow mesenchymal stem cell fate: insight into mechanical regulation and bone formation

Cell & Bioscience ◽

10.1186/s13578-021-00601-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yuanxiu Sun ◽

Yu Yuan ◽

Wei Wu ◽

Le Lei ◽

Lingli Zhang

Keyword(s):

Bone Marrow ◽

Cell Fate ◽

Differentiation Potential ◽

Stem Cell Fate ◽

Proliferation And Differentiation ◽

Marrow Mesenchymal Stem Cells ◽

Adipocytic Differentiation ◽

Regulatory Effects ◽

Insight Into ◽

Mechanical Regulation

AbstractBone marrow mesenchymal stem cells (BMSCs) refer to a heterogeneous population of cells with the capacity for self-renewal. BMSCs have multi-directional differentiation potential and can differentiate into chondrocytes, osteoblasts, and adipocytes under specific microenvironment or mechanical regulation. The activities of BMSCs are closely related to bone quality. Previous studies have shown that BMSCs and their lineage-differentiated progeny (for example, osteoblasts), and osteocytes are mechanosensitive in bone. Thus, a goal of this review is to discuss how these ubiquious signals arising from mechanical stimulation are perceived by BMSCs and then how the cells respond to them. Studies in recent years reported a significant effect of locomotion on the migration, proliferation and differentiation of BMSCs, thus, contributing to our bone mass. This regulation is realized by the various intersecting signaling pathways including RhoA/Rock, IFG, BMP and Wnt signalling. The mechanoresponse of BMSCs also provides guidance for maintaining bone health by taking appropriate exercises. This review will summarize the regulatory effects of locomotion/mechanical loading on BMSCs activities. Besides, a number of signalling pathways govern MSC fate towards osteogenic or adipocytic differentiation will be discussed. The understanding of mechanoresponse of BMSCs makes the foundation for translational medicine.

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Bone marrow stromal cells from MDS and AML patients show increased adipogenic potential with reduced Delta-like-1 expression

Scientific Reports ◽

10.1038/s41598-021-85122-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marie-Theresa Weickert ◽

Judith S. Hecker ◽

Michèle C. Buck ◽

Christina Schreck ◽

Jennifer Rivière ◽

...

Keyword(s):

Bone Marrow ◽

Cell Fate ◽

Stromal Cells ◽

Adipogenic Differentiation ◽

Cell Types ◽

Bone Marrow Niche ◽

Differentiation Potential ◽

Hematopoietic Stem ◽

Bm Niche

AbstractMyelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell disorders with a poor prognosis, especially for elderly patients. Increasing evidence suggests that alterations in the non-hematopoietic microenvironment (bone marrow niche) can contribute to or initiate malignant transformation and promote disease progression. One of the key components of the bone marrow (BM) niche are BM stromal cells (BMSC) that give rise to osteoblasts and adipocytes. It has been shown that the balance between these two cell types plays an important role in the regulation of hematopoiesis. However, data on the number of BMSC and the regulation of their differentiation balance in the context of hematopoietic malignancies is scarce. We established a stringent flow cytometric protocol for the prospective isolation of a CD73+ CD105+ CD271+ BMSC subpopulation from uncultivated cryopreserved BM of MDS and AML patients as well as age-matched healthy donors. BMSC from MDS and AML patients showed a strongly reduced frequency of CFU-F (colony forming unit-fibroblast). Moreover, we found an altered phenotype and reduced replating efficiency upon passaging of BMSC from MDS and AML samples. Expression analysis of genes involved in adipo- and osteogenic differentiation as well as Wnt- and Notch-signalling pathways showed significantly reduced levels of DLK1, an early adipogenic cell fate inhibitor in MDS and AML BMSC. Matching this observation, functional analysis showed significantly increased in vitro adipogenic differentiation potential in BMSC from MDS and AML patients. Overall, our data show BMSC with a reduced CFU-F capacity, and an altered molecular and functional profile from MDS and AML patients in culture, indicating an increased adipogenic lineage potential that is likely to provide a disease-promoting microenvironment.

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Mechanism of Action of Diallyl Sulphide in Ameliorating the Hematopoietic Radiation Injury

Journal of Health and Allied Sciences NU ◽

10.1055/s-0041-1730094 ◽

2021 ◽

Author(s):

Omika Katoch ◽

Mrinalini Tiwari ◽

Namita Kalra ◽

Paban K. Agrawala

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Progenitor Cells ◽

Hematopoietic Stem ◽

Proliferation And Differentiation ◽

Stem And Progenitor Cells ◽

Radiation Induced ◽

Medicinal Properties ◽

Marrow Cellularity

AbstractDiallyl sulphide (DAS), the pungent component of garlic, is known to have several medicinal properties and has recently been shown to have radiomitigative properties. The present study was performed to better understand its mode of action in rendering radiomitigation. Evaluation of the colonogenic ability of hematopoietic progenitor cells (HPCs) on methocult media, proliferation and differentiation of hematopoietic stem cells (HSCs), and transplantation of stem cells were performed. The supporting tissue of HSCs was also evaluated by examining the histology of bone marrow and in vitro colony-forming unit–fibroblast (CFU-F) count. Alterations in the levels of IL-5, IL-6 and COX-2 were studied as a function of radiation or DAS treatment. It was observed that an increase in proliferation and differentiation of hematopoietic stem and progenitor cells occurred by postirradiation DAS administration. It also resulted in increased circulating and bone marrow homing of transplanted stem cells. Enhancement in bone marrow cellularity, CFU-F count, and cytokine IL-5 level were also evident. All those actions of DAS that could possibly add to its radiomitigative potential and can be attributed to its HDAC inhibitory properties, as was observed by the reversal radiation induced increase in histone acetylation.

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IMMU-50. GLIOBLASTOMA MANIPULATES HEMATOPOIETIC STEM CELL DIFFERENTIATION OUTCOMES AND DRIVES ALTERED IMMUNE RECONSTITUTION

Neuro-Oncology ◽

10.1093/neuonc/noab196.409 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi104-vi104

Author(s):

Bayli DiVita Dean ◽

Tyler Wildes ◽

Joseph Dean ◽

David Shin ◽

Connor Francis ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Progenitor Cells ◽

Rna Sequencing ◽

Cell Fate ◽

Immune Reconstitution ◽

Stem Cell Differentiation ◽

Cell Fate Determination ◽

Hematopoietic Stem ◽

Fate Determination

Abstract INTRODUCTION Bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) give rise to the cellular components of the immune system. Unfortunately, immune reconstitution from HSPCs are negatively impacted by solid cancers, including high-grade gliomas. For example, an expansion of myeloid progenitor cells has been previously described across several cancers that originate outside the CNS. A similar expansion of MDSCs coupled with diminished T cell function has also been described in the peripheral blood of patients with newly-diagnosed GBM. Alterations in both lymphoid and myeloid compartments due to CNS malignancy led us to determine how intracranial gliomas impact HSPCs in both their capacity to reconstitute the immune compartment and in their cell fate determination. This is important to better understand the impact of gliomas on immunity and how we can leverage these findings to better develop cellular immunotherapeutics. METHODS HSPCs were isolated from bone marrow of C57BL/6 mice with orthotopic KR158B glioma, or age-matched naïve mice. Experiments were conducted to compare relative changes in: gene expression (RNA-sequencing), precursor frequencies, cell fate determination, and cellular function of cells derived from HSPCs of glioma-bearing mice. RESULTS RNA-sequencing revealed 700+ genes whose expression was significantly up- or downregulated in HSPCs from glioma-bearing mice, particularly those involved with stemness and metabolic activity. Importantly, HSPCs from glioma-bearing mice expressed upregulation of genes involved in myelopoiesis relative to naïve mice. This was coupled with an expansion of granulocyte macrophage precursors (GMPs), the progenitors to gMDSCs. Next, differentiation assays revealed that HSPCs from glioma-bearing mice had higher propensity of differentiating into MDSC under homeostatic conditions relative to controls both in vitro and in vivo. Furthermore, mice bearing intracranial gliomas possess an expansion of MDSCs which are more suppressive on T cell proliferation and hinders T cell-mediated tumor cell killing relative to MDSCs derived from naïve control mice.

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Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q− polycythemia vera

Blood ◽

10.1182/blood-2010-02-270611 ◽

2010 ◽

Vol 116 (15) ◽

pp. 2812-2821 ◽

Cited By ~ 39

Author(s):

Fabiana Perna ◽

Nadia Gurvich ◽

Ruben Hoya-Arias ◽

Omar Abdel-Wahab ◽

Ross L. Levine ◽

...

Keyword(s):

Polycythemia Vera ◽

Progenitor Cells ◽

Cell Fate ◽

Myeloproliferative Neoplasms ◽

Erythroid Differentiation ◽

Polycomb Group ◽

Human Cord Blood ◽

Hematopoietic Stem ◽

Cell Fate Decisions ◽

Cd34 Cells

Abstract L3MBTL1, the human homolog of the Drosophila L(3)MBT polycomb group tumor suppressor gene, is located on chromosome 20q12, within the common deleted region identified in patients with 20q deletion-associated polycythemia vera, myelodysplastic syndrome, and acute myeloid leukemia. L3MBTL1 is expressed within hematopoietic CD34+ cells; thus, it may contribute to the pathogenesis of these disorders. To define its role in hematopoiesis, we knocked down L3MBTL1 expression in primary hematopoietic stem/progenitor (ie, CD34+) cells isolated from human cord blood (using short hairpin RNAs) and observed an enhanced commitment to and acceleration of erythroid differentiation. Consistent with this effect, overexpression of L3MBTL1 in primary hematopoietic CD34+ cells as well as in 20q− cell lines restricted erythroid differentiation. Furthermore, L3MBTL1 levels decrease during hemin-induced erythroid differentiation or erythropoietin exposure, suggesting a specific role for L3MBTL1 down-regulation in enforcing cell fate decisions toward the erythroid lineage. Indeed, L3MBTL1 knockdown enhanced the sensitivity of hematopoietic stem/progenitor cells to erythropoietin (Epo), with increased Epo-induced phosphorylation of STAT5, AKT, and MAPK as well as detectable phosphorylation in the absence of Epo. Our data suggest that haploinsufficiency of L3MBTL1 contributes to some (20q−) myeloproliferative neoplasms, especially polycythemia vera, by promoting erythroid differentiation.

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