scholarly journals Interleukin-7 is necessary to maintain the B cell potential in common lymphoid progenitors

2005 ◽  
Vol 201 (6) ◽  
pp. 971-979 ◽  
Author(s):  
Sheila Dias ◽  
Hamilton Silva ◽  
Ana Cumano ◽  
Paulo Vieira
Keyword(s):  
B Cell ◽  
B Cell Differentiation ◽  
Wild Type ◽  
Cell Potential ◽  
Differentiation Potential ◽  
Lymphoid Lineage ◽  
Interleukin 7 ◽  
Multipotent Progenitors ◽  
Early B Cell Factor ◽  
Deficient Mice

Interleukin-7 (IL-7) promotes survival and expansion of lymphoid precursors. We show here that, in addition, IL-7 has a fundamental role, as early as the stage of the multipotent (B/T/NK) common lymphoid progenitor (CLP), in maintaining the B cell differentiation program open. CLPs generated in the absence of IL-7 have normal T/NK differentiation potential, but severely impaired B potential. Accordingly, CLPs from IL-7–deficient mice express lower amounts of early B cell factor (EBF) and Pax5 than wild-type CLPs, but similar amounts of GATA-3. Importantly, induced overexpression of EBF is sufficient to restore the B potential in these cells. These results indicate that IL-7 directs commitment of CLPs by modulating EBF expression. This is the first example of a cytokine influencing lymphoid lineage commitment in multipotent progenitors and highlights the relevance of the expression of a functional IL-7 receptor at the CLP stage.

scholarly journals Balance between Id and E proteins regulates myeloid-versus-lymphoid lineage decisions

Blood ◽  
2009 ◽  
Vol 113 (5) ◽  
pp. 1016-1026 ◽  
Author(s):  
Shawn W. Cochrane ◽  
Ying Zhao ◽  
Robert S. Welner ◽  
Xiao-Hong Sun
Keyword(s):  
Transcription Factors ◽  
B Cell ◽  
Cell Fate ◽  
Intracellular Signaling ◽  
Specific Gene ◽  
B Cell Differentiation ◽  
E Proteins ◽  
Lymphoid Lineage ◽  
E Protein ◽  
Multipotent Progenitors

Abstract Hematopoiesis consists of a series of lineage decisions controlled by specific gene expression that is regulated by transcription factors and intracellular signaling events in response to environmental cues. Here, we demonstrate that the balance between E-protein transcription factors and their inhibitors, Id proteins, is important for the myeloid-versus-lymphoid fate choice. Using Id1-GFP knockin mice, we show that transcription of the Id1 gene begins to be up-regulated at the granulocyte-macrophage progenitor stage and continues throughout myelopoiesis. Id1 expression is also stimulated by cytokines favoring myeloid differentiation. Forced expression of Id1 in multipotent progenitors promotes myeloid development and suppresses B-cell formation. Conversely, enhancing E-protein activity by expressing a variant of E47 resistant to Id-mediated inhibition prevents the myeloid cell fate while driving B-cell differentiation from lymphoid-primed multipotent progenitors. Together, these results suggest a crucial function for E proteins in the myeloid-versus-lymphoid lineage decision.

scholarly journals Optimized Protocols for in Vitro T Cell-Dependent and T Cell-Independent Activation for B Cell Differentiation Studies Using Limited Cells

2021 ◽  
Author(s):  
Casper Marsman ◽  
Dorit Verhoeven
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Formation ◽  
B Cell Differentiation ◽  
Differentiation Potential ◽  
Human B Cell

Background/methods: For mechanistic studies, in vitro human B cell differentiation and generation of plasma cells are invaluable techniques. However, the heterogeneity of both T cell-dependent (TD) and T cell-independent (TI) stimuli and the disparity of culture conditions used in existing protocols makes interpretation of results challenging. The aim of the present study was to achieve the most optimal B cell differentiation conditions using isolated CD19+ B cells and PBMC cultures. We addressed multiple seeding densities, different durations of culturing and various combinations of TD stimuli and TI stimuli including B cell receptor (BCR) triggering. B cell expansion, proliferation and differentiation was analyzed after 6 and 9 days by measuring B cell proliferation and expansion, plasmablast and plasma cell formation and immunoglobulin (Ig) secretion. In addition, these conditions were extrapolated using cryopreserved cells and differentiation potential was compared. Results: This study demonstrates improved differentiation efficiency after 9 days of culturing for both B cell and PBMC cultures using CD40L and IL-21 as TD stimuli and 6 days for CpG and IL-2 as TI stimuli. We arrived at optimized protocols requiring 2500 and 25.000 B cells per culture well for TD and TI assays, respectively. The results of the PBMC cultures were highly comparable to the B cell cultures, which allows dismissal of additional B cell isolation steps prior to culturing. In these optimized TD conditions, the addition of anti-BCR showed little effect on phenotypic B cell differentiation, however it interferes with Ig secretion measurements. Addition of IL-4 to the TD stimuli showed significantly lower Ig secretion. The addition of BAFF to optimized TI conditions showed enhanced B cell differentiation and Ig secretion in B cell but not in PBMC cultures. With this approach, efficient B cell differentiation and Ig secretion was accomplished when starting from fresh or cryopreserved samples. Conclusion: Our methodology demonstrates optimized TD and TI stimulation protocols for more indepth analysis of B cell differentiation in primary human B cell and PBMC cultures while requiring low amounts of B cells, making them ideally suited for future clinical and research studies on B cell differentiation of patient samples from different cohorts of B cell-mediated diseases.

scholarly journals Early B Cell Factor Promotes B Lymphopoiesis with Reduced Interleukin 7 Responsiveness in the Absence of E2A

2004 ◽  
Vol 199 (12) ◽  
pp. 1689-1700 ◽  
Author(s):  
Christopher S. Seet ◽  
Rachel L. Brumbaugh ◽  
Barbara L. Kee
Keyword(s):  
Transcription Factors ◽  
B Cell ◽  
B Lymphopoiesis ◽  
Protein Activity ◽  
E Proteins ◽  
Helix Loop Helix ◽  
Interleukin 7 ◽  
E Protein ◽  
B Lineage ◽  
Early B Cell Factor

The basic helix-loop-helix transcription factors encoded by the E2A gene function at the apex of a transcriptional hierarchy involving E2A, early B cell factor (EBF), and Pax5, which is essential for B lymphopoiesis. In committed B lineage progenitors, E2A proteins have also been shown to regulate many lineage-associated genes. Herein, we demonstrate that the block in B lymphopoiesis imposed by the absence of E2A can be overcome by expression of EBF, but not Pax5, indicating that EBF is the essential target of E2A required for development of B lineage progenitors. Our data demonstrate that EBF, in synergy with low levels of alternative E2A-related proteins (E proteins), is sufficient to promote expression of most B lineage genes. Remarkably, however, we find that E2A proteins are required for interleukin 7–dependent proliferation due, in part, to a role for E2A in optimal expression of N-myc. Therefore, high levels of E protein activity are essential for the activation of EBF and N-myc, whereas lower levels of E protein activity, in synergy with other B lineage transcription factors, are sufficient for expression of most B lineage genes.

CtBP1 Is a Novel and Essential Corepressor for BCL6 Autoregulation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3581-3581
Author(s):  
Lourdes M. Mendez ◽  
Jose Polo ◽  
Melissa Krupski ◽  
Jessica Yu ◽  
Ari M. Melnick ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Cell Lines ◽  
Cell Biology ◽  
Target Genes ◽  
Point Mutations ◽  
B Cell Lymphoma ◽  
B Cell Differentiation ◽  
Wild Type ◽  
Negative Autoregulation

Abstract BCL6 is POZ/BTB transcription repressor that is required for the germinal center (GC)- stage of B cell development and its deregulated expression underlies the development of many GC-derived B cell lymphomas such as diffuse large B cell lymphoma (DLBCL). BCL6 carries out its biological function by repressing target genes involved in various aspects of B cell biology such as DNA damage response, cell-cycle regulation and plasma cell differentiation. Recent publications indicate that BCL6 differentially utilizes its corepressor partners to silence target genes involved in different biological processes. Negative autoregulation of BCL6 is likely to play an important role in B-cell differentiation, and is frequently disrupted in DLBCL due to translocation or point mutation of the BCL6 promoter. However, from a mechanistic standpoint, it is not known how BCL6 mediates negative autoregulation. BCL6 is reported to repress its target genes through binding of the SMRT, NCoR and BCoR corepressors to its N-terminal POZ domain and through binding of the MTA3 and HDAC2 corepressors to its second repression domain. However, a BCL6 mutant unable to bind these corepressors retained near wild-type repression activity on the BCL6 promoter. The expression of endogenous BCL6 was unchanged in DLBCL cell lines treated with BCL6 Peptide Inhibitor, which selectively disrupts the association between BCL6 and its POZ domain corepressors, or with MTA3 siRNA. This led us to consider the possibility that BCL6 autoregulation proceeds through a novel corepressor. Several POZ transcription factors can interact with CtBP as their corepressor. We found BCL6 and CtBP can interact in both the ectopically expressed and endogenous settings in DLBCL cells. Moreover, our ChIP experiments demonstrate that CtBP is present in the 5′UTR of BCL6 at sites that were previously shown by us and others to mediate BCL6 negative autoregulation. Nearly half of DLBCL patients are estimated to carry translocations and “activating” point mutations in the 5′UTR of BCL6 which allow negative autoregulation to be bypassed. In DLBCL cell lines carrying BCL6 promoter mutations or translocations, CtBP was preferentially bound to the wild-type BCL6 allele. Moreover, CtBP siRNA specifically derepressed the wild-type allele sparing the translocated BCL6 allele driven by heterologous promoters. This allelic analysis of BCL6 is consistent with a model in which BCL6 recruits CtBP to carry out negative autoregulation. Tiling ChIP-on-chip of BCL6 target genes showed colocalization of CtBP in a BCL6 repression complex at only a subset of target genes, including BCL6. However, the BCL6 locus was the only target dependent exclusively on CtBP for repression. In an effort to address the corepressor requirements of BCL6 autoregulation, we have uncovered a novel BCL6 corepressor, CtBP. Our results substantiate the growing body of evidence that BCL6’s mechanism of repression is dynamic, selectively calling upon corepressors to silence different cohorts of target genes perhaps reflecting segregation of biological functions. Our study provides new insight into normal BCL6-driven biology and also informs BCL6-targeted lymphoma therapies.

Trisomy of the Down Syndrome Critical Region Suppresses Precursor B-Cell Differentiation and Promotes B-Cell Transformation Associated with Altered Expression of Polycomb Repressor Complex 2 Targets

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 115-115
Author(s):  
Andrew A. Lane ◽  
Diederik van Bodegom ◽  
Bjoern Chapuy ◽  
Gabriela Alexe ◽  
Timothy J Sullivan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Transformation ◽  
B Cell Differentiation ◽  
Wild Type ◽  
Repressor Complex

Abstract Abstract 115 Extra copies of chromosome 21 (polysomy 21) is the most common somatic aneuploidy in B-cell acute lymphoblastic leukemia (B-ALL), including >90% of cases with high hyperdiploidy. In addition, children with Down syndrome (DS) have a 20-fold increased risk of developing B-ALL, of which ∼60% harbor CRLF2 rearrangements. To examine these associations within genetically defined models, we investigated B-lineage phenotypes in Ts1Rhr mice, which harbor triplication of 31 genes syntenic with the DS critical region (DSCR) on human chr.21. Murine pro-B cell (B220+CD43+) development proceeds sequentially through “Hardy fractions” defined by cell surface phenotype: A (CD24−BP-1−), B (CD24+BP-1−) and then C (CD24+BP-1+). Compared with otherwise isogenic wild-type littermates, Ts1Rhr bone marrow harbored decreased percentages of Hardy fraction B and C cells, indicating that DSCR triplication is sufficient to disrupt the Hardy A-to-B transition. Of note, the same phenotype was reported in human DS fetal liver B-cells, which have a block between the pre-pro- and pro-B cell stages (analogous to Hardy A-to-B). To determine whether DSCR triplication affects B-cell proliferation in vitro, we analyzed colony formation and serial replating in methylcellulose cultures. Ts1Rhr bone marrow (B6/FVB background) formed 2–3-fold more B-cell colonies in early passages compared to bone marrow from wild-type littermates. While wild-type B-cells could not serially replate beyond 4 passages, Ts1Rhr B-cells displayed indefinite serial replating (>10 passages). Ts1Rhr mice do not spontaneously develop leukemia, so we utilized two mouse models to determine whether DSCR triplication cooperates with leukemogenic oncogenes in vivo. First, we generated Eμ-CRLF2 F232C mice, which express the constitutively active CRLF2 mutant solely within B-cells. Like Ts1Rhr B-cells, (but not CRLF2 F232C B-cells) Ts1Rhr/CRLF2 F232C cells had indefinite serial replating potential. In contrast with Ts1Rhr B-cells, Ts1Rhr/CRLF2 F232C B-cells also engrafted into NOD.Scid.IL2Rγ−/− mice and caused fatal and serially transplantable B-ALL. Second, we retrovirally transduced BCR-ABL1 into unselected bone marrow from wild-type and Ts1Rhr mice and transplanted into irradiated wild-type recipients. Transplantation of transduced Ts1Rhr cells (106, 105, or 104) caused fatal B-ALL in recipient mice with shorter latency and increased penetrance compared to recipients of the same number of transduced wild-type cells. By Poisson calculation, the number of B-ALL initiating cells in transduced Ts1Rhr bone marrow was ∼4-fold higher than in wild-type animals (1:60 vs 1:244, P=0.0107). Strikingly, transplantation of individual Hardy A, B, and C fractions after sorting and BCR-ABL1 transduction demonstrated that the increased leukemia-initiating capacity almost completely resides in the Ts1Rhr Hardy B fraction; i.e., the same subset suppressed during Ts1Rhr B-cell differentiation. To define transcriptional determinants of these phenotypes, we performed RNAseq of Ts1Rhr and wild-type B cells in methylcellulose culture (n=3 biologic replicates per genotype). As expected, Ts1Rhr colonies had ∼1.5-fold higher RNA abundance of expressed DSCR genes. We defined a Ts1Rhr signature of the top 200 genes (false discovery rate (FDR) <0.25) differentially expressed compared with wild-type cells. Importantly, this Ts1Rhr signature was significantly enriched (P=0.02) in a published gene expression dataset of DS-ALL compared with non-DS-ALL (Hertzberg et al., Blood 2009). Query of >2,300 signatures in the Molecular Signatures Database (MSigDB) C2 Chemical and Genetic Perturbations with the Ts1Rhr signature identified enrichment in multiple gene sets of polycomb repressor complex (PRC2) targets and H3K27 trimethylation. Most notably, SUZ12 targets within human embryonic stem cells were more highly expressed in Ts1Rhr cells (P=1.2×10−6, FDR=0.003) and the same SUZ12 signature was enriched in patients with DS-ALL compared to non-DS-ALL (P=0.007). In summary, DSCR triplication directly suppresses precursor B-cell differentiation and promotes B-cell transformation both in vitro and by cooperating with proliferative alterations such as CRLF2 activation and BCR-ABL1 in vivo. Pharmacologic modulation of H3K27me3 effectors may overcome the pro-leukemogenic effects of polysomy 21. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Immunoglobulin recombinase gene activity is modulated reciprocally by interleukin 7 and CD19 in B cell progenitors.

1995 ◽  
Vol 182 (4) ◽  
pp. 973-982 ◽  
Author(s):  
L G Billips ◽  
C A Nuñez ◽  
F E Bertrand ◽  
A K Stankovic ◽  
G L Gartland ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Immunoglobulin Gene ◽  
B Cell Differentiation ◽  
Interleukin 7 ◽  
Cross Linkage ◽  
Recombinase Gene ◽  
Rag 1 ◽  
B Lineage

Bone marrow stromal cells promote B cell development involving recombinase gene-directed rearrangement of the immunoglobulin genes. We observed that the stromal cell-derived cytokine interleukin 7 (IL-7) enhances the expression of CD19 molecules on progenitor B-lineage cells in human bone marrow samples and downregulates the expression of terminal deoxynucleotidyl transferase (TdT) and the recombinase-activating genes RAG-1 and RAG-2. Initiation of the TdT downregulation on the first day of treatment, CD19 upregulation during the second day, and RAG-1 and RAG-2 downmodulation during the third day implied a cascade of IL-7 effects. While CD19 ligation by divalent antibodies had no direct effect on TdT or RAG gene expression, CD19 cross-linkage complete blocked the IL-7 downregulation of RAG expression without affecting the earlier TdT response. These results suggest that signals generated through CD19 and the IL-7 receptor could modulate immunoglobulin gene rearrangement and repertoire diversification during the early stages of B cell differentiation.

scholarly journals Essential Role of Phospholipase Cγ2 in Early B-Cell Development and Myc-Mediated Lymphomagenesis

2006 ◽  
Vol 26 (24) ◽  
pp. 9364-9376 ◽  
Author(s):  
Renren Wen ◽  
Yuhong Chen ◽  
Li Bai ◽  
Guoping Fu ◽  
James Schuman ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Cell Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Receptor ◽  
Wild Type ◽  
Interleukin 7

ABSTRACT Phospholipase Cγ2 (PLCγ2) is a critical signaling effector of the B-cell receptor (BCR). Here we show that PLCγ2 deficiency impedes early B-cell development, resulting in an increase of B220+ CD43+ BP-1+ CD24hi pre-BCR+ large pre-B cells. PLCγ2 deficiency impairs pre-BCR-mediated functions, leading to enhanced interleukin-7 (IL-7) signaling and elevated levels of RAGs in the selected large pre-B cells. Consequently, PLCγ2 deficiency renders large pre-B cells susceptible to transformation, resulting in dramatic acceleration of Myc-induced lymphomagenesis. PLCγ2 −/− Eμ-Myc transgenic mice mainly develop lymphomas of B220+ CD43+ BP-1+ CD24hi pre-BCR+ large pre-B-cell origin, which are uncommon in wild-type Eμ-Myc transgenics. Furthermore, lymphomas from PLCγ2 −/− Eμ-Myc transgenic mice exhibited a loss of p27Kip1 and often displayed alterations in Arf or p53. Thus, PLCγ2 plays an important role in pre-BCR-mediated early B-cell development, and its deficiency leads to markedly increased pools of the most at-risk large pre-B cells, which display hyperresponsiveness to IL-7 and express high levels of RAGs, making them prone to secondary mutations and Myc-induced malignancy.

scholarly journals Are B Lymphocytes of Importance in Severe Staphylococcus aureus Infections?

2000 ◽  
Vol 68 (5) ◽  
pp. 2431-2434 ◽  
Author(s):  
Inger Gjertsson ◽  
Olof Hörnquist Hultgren ◽  
Martin Stenson ◽  
Rikard Holmdahl ◽  
Andrzej Tarkowski
Keyword(s):  
Staphylococcus Aureus ◽  
B Cells ◽  
B Cell ◽  
Interleukin 4 ◽  
Wild Type ◽  
Toxic Shock ◽  
Toxic Shock Syndrome Toxin ◽  
Deficient Mice ◽  
Wild Type Control

ABSTRACT To investigate the role of B cells in experimental, superantigen-mediated Staphylococcus aureus arthritis and sepsis, we used gene-targeted B-cell-deficient mice. The mice were inoculated intravenously with a toxic shock syndrome toxin 1 (TSST-1)-producing S. aureus strain. The B-cell-deficient and thus agamma-globulinemic mice showed striking similarities to the wild-type control animals with respect to the development of arthritis, the mortality rate, and the rate of bacterial clearance. Surprisingly, we found that the levels of gamma interferon in serum were significantly lower (P < 0.0001) in B-cell-deficient mice than in the controls, possibly due to impaired superantigen presentation and a diminished expression of costimulatory molecules. In contrast, the levels of interleukin-4 (IL-4), IL-6, and IL-10 in serum were equal in both groups. Our findings demonstrate that neither mature B cells nor their products significantly contribute to the course ofS. aureus-induced septic arthritis.

scholarly journals Sox4 Is Required for the Formation and Maintenance of Multipotent Progenitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1577-1577 ◽  
Author(s):  
Hong Zhang ◽  
Min Ye ◽  
Robert S. Welner ◽  
Daniel G. Tenen
Keyword(s):  
Progenitor Cells ◽  
Absolute Number ◽  
Brdu Incorporation ◽  
Binding Motif ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Genetic Ablation ◽  
Qpcr Analysis ◽  
Multipotent Progenitors ◽  
Deficient Mice

Abstract Introduction Hematopoiesis is maintained by a hierarchical system, whereas aberrant control of hematopoiesis is the underlying cause of many diseases. Within the hematopoietic hierarchy, hematopoietic stem cells (HSCs) give rise to multipotent progenitors that have lost their self-renewal capacity but remain multipotent to differentiate into mature blood cells. However, the precise molecular mechanisms that modulate this transition are not fully understood yet. Results We recently discovered that genetic ablation of SRY sex determining region Y-box 4 gene (Sox4) in the murine hematopoietic system resulted in dramatic loss of multipotent progenitor population (CD48+CD150-Lin-kit+Sca1+, or CD48+CD150-LSK) both relatively (to the total LSK population) and in absolute number. Interestingly, the absolute number of HSCs (CD48-CD150+Lin-kit+Sca1+, or SLAM+LSK) in these conditional Sox4-deficient mice was comparable to their wild-type counterparts. Transcriptional factor Sox4 belongs to the high-mobility group (HMG) domain superfamily which also includes other Sox proteins, TCF-1 (T-cell factor 1) and LEF-1 (lymphoid enhancer factor 1). Sox4 has been implicated in leukemogenesis and may potentially contribute to stem cell properties. Nevertheless, the precise roles of Sox4 in hematopoietic stem/progenitor cells and the underlying mechanisms have not been defined yet. Further analysis of stem/progenitor compartment defined by Flt3 and CD34 expression demonstrated a major loss in lymphoid-primed multipotent progenitors (LMPPs) (CD34+Flt3+LSK) with relatively normal formation of LT-HSCs (CD34-Flt3-LSK) and ST-HSCs (CD34+Flt3-LSK) upon the loss of Sox4, suggesting that Sox4 is essential for the development from HSCs to multipotent progenitors. Such observation is in line with the expression pattern of Sox4. Quantitative PCR (qPCR) analysis of wild-type mice revealed that expression of Sox4 increased from HSCs to multipotent progenitors which expressed Sox4 at the highest level among all the hematopoietic compartments. Studies of biological behaviors further indicateed that disruption of Sox4 had no effect on proliferative capacity of HSCs and multipotent progenitors, as evidenced by BrdU incorporation assay. However, Annexin V/propidium iodide staining revealed an increased frequency of apoptotic multipotent progenitors, but not that of HSCs upon the ablation of Sox4. In a transplantation setting, although Sox4-deficient LSKs homed appropriately to the bone marrow, they exhibited severely impaired ability to give rise to multipotent progenitors, but contributed normally to HSCs compared to the wild-type donors. Among a set of genes crucial to the biological properties of stem/progenitor cells, qPCR analysis revealed that upon the loss of Sox4, only the levels of Ikaros1 and Ikaros2, the two major Ikaros isoforms in stem/progenitor cells, were downregulated specifically in multipotent progenitors, but remained normal in HSCs. Intriguingly, in a reminiscent manner of Sox4-deficient mice, mice lacking both Ikaros 1 and Ikaros 2 proteins, also exhibited disrupted B cell development and selectively impaired LMPPs. Previous study identified an enhancer of Ikaros locus as the only cis-regulatory element that was capable of stimulating reporter expression in the LMPPs. Our sequence analysis revealed a highly conserved Sox4 binding motif within this enhancer, therefore potentially connecting Sox4 with the known regulatory networks that modulate the differentiation of HSCs. Currently, we are working on (1) confirming the direct transcriptional regulation of Ikaros by Sox4; (2) assessing whether Ikaros mediates the functions of Sox4 in the formation or maintenance of the multipotent progenitors population in vivo; and (3) delineating the downstream regulatory network of Sox4 in stem/progenitor cells. Conclusion In summary, out study reveals a novel role for Sox4 gene in early hematopoiesis and brings important insights into the regulatory mechanisms underlying the commitment of HSCs toward multipotent progenitors. Disclosures No relevant conflicts of interest to declare.

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