Ikaros limits basophil development by suppressing C/EBP-α expression

Rao, Kavitha N.; Smuda, Craig; Gregory, Gregory D.; Min, Booki; Brown, Melissa A.

doi:10.1182/blood-2013-04-494625

Cited by 31 publications

(30 citation statements)

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“…24 In a separate study, another myeloid and lymphoid transcription factor, Ikaros (encoded by Ikzf1), and its downstream factor, Hes1, were found to epigenetically downregulate Cebpa gene expression and to thereby limit the differentiation of basophils. 34 These studies, together with our findings, indicate that the Cebpa gene can be repressed by several molecular mechanisms. Although the origin and developmental pathways of mast cells remain controversial, [36][37][38] there is solid evidence that the Cebpa gene is repressed throughout mast cell development.…”

Section: Discussionmentioning

confidence: 77%

“…Although the origin and developmental pathways of mast cells remain controversial, [36][37][38] there is solid evidence that the Cebpa gene is repressed throughout mast cell development. 23,24,34,36 We speculate that the antagonism between GATA2 and C/EBPa may not be involved in the basophil-mast cell fate decision, because both factors were shown to be required for normal basophil development. MITF and/or Ikaros might play a major role in repressing the Cebpa gene at this stage.…”

Section: Discussionmentioning

confidence: 99%

“…The conserved GATA binding sites were found in the 2 cis-acting regions, referred to as 12 and 137 kb, and the latter has been reported as an enhancer activated by RUNX1 in an immature myeloid cell line, 32Dcl3. [33][34][35] Interestingly, there is a 34-bp region containing the GATA, RUNX1, and PU.1 binding sites in close Figure 6A; supplemental Figure 4). GATA2 binding to this region, but not to the promoter, was detected in BMMCs, and this binding activity was significantly reduced after 4-OHT treatment ( Figure 6B).…”

Section: Gata2 Binds To the 137-kb Enhancer Chromatin Region Of The Mmentioning

confidence: 99%

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GATA2 is critical for the maintenance of cellular identity in differentiated mast cells derived from mouse bone marrow

Ohmori

Moriguchi

Noguchi

et al. 2015

Blood

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Gata2 Binds To the 137-kb Enhancer Chromatin Region Of The Mmentioning

confidence: 99%

See 1 more Smart Citation

GATA2 is critical for the maintenance of cellular identity in differentiated mast cells derived from mouse bone marrow

Ohmori

Moriguchi

Noguchi

et al. 2015

Blood

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“…Supporting this idea, IKZF1 overexpression in transgenic mice represses GATA1 expression, implying that loss of IKZF1 function may increase GATA1 function. 21 Taken together, we find evidence for IKZF1 as a tumor suppressor gene in pediatric acute myeloid leukemia and suggest that IKZF1 deletion might be one of the driving events of monosomy 7 in various myeloid diseases. …”

Section: A B C D E Fmentioning

confidence: 88%

“…18,20 Although IKZF1 is not required for the initial differentiation towards granulocytes and monocytes, IKZF1 represses differentiation of the basophilic granulocyte lineage and promotes early maturation and survival of the neutrophil granulocyte lineage. 17,21,22 In pediatric AML, monosomy 7 is found in only 4%-5% of patients. The 5-year OS and EFS of pediatric AML patients with monosomy 7 with or without additional cytogenetic or chromosomal aberrations are poor.…”

Section: Introductionmentioning

confidence: 99%

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nby controlling transcriptional regulators, such as GATA1 and RUNX1. 18,20 Although IKZF1 is not required for the initial differentiation towards granulocytes and monocytes, IKZF1 represses differentiation of the basophilic granulocyte lineage and promotes early maturation and survival of the neutrophil granulocyte lineage. 17,21,22 In pediatric AML, monosomy 7 is found in only 4%-5% of patients. The 5-year OS and EFS of pediatric AML patients with monosomy 7 with or without additional cytogenetic or chromosomal aberrations are poor. 23 In adult AML, monosomy 7 is the most frequent single monosomy and has a similar poor 4-year OS as compared to other single autosomal monosomies. 24 Deletions of the short arm of chromosome 7, 7p (del7p) were recurrently found in adult de novo AML and secondary AML developed from myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN). [25][26][27] Furthermore, 7p deletions were mapped to the IKZF1 locus and it was shown that loss of IKZF1 is acquired during the progression of MPN to secondairy AML, indicating that loss of IKZF1 contributes to the transformation from MPN to AML. 25 Together, these studies demonstrate that IKZF1 may play a role in myeloid differentiation and that loss of IKZF1 may contribute to myeloid oncogenesis. We, therefore, hypothesized that, in pediatric AML patients with monosomy 7, IKZF1 may be an important player. In this study, we analyzed the frequency of IKZF1 deletions in a pediatric AML cohort, and studied the difference in gene expression of cases with focal IKZF1 deletions, and cases with monosomy 7. Methods Patients' samplesSamples were provided by the Dutch Childhood Oncology Group (DCOG, the Netherlands), the AML-Berliner-FrankfurtMünster Study Group (Germany and Czech Republic), the SaintLouis Hospital (France), and the Royal Hospital for Sick Children (UK). Isolation of genomic DNA and total cellular RNA was performed using Trizol reagent. Each study group provided morphological and cytogenetic classification and clinical data. Institutional review board approval for these studies had been obtained in the participating centers. Detection of deletions and mutations of IKZF1Multiplex ligation-dependent probe amplification (MLPA) was performed using the p335-B1;ALL-IKZF1 kit (MRC Holland, Amsterdam, the Netherlands; data available at http: //www.mlpa.com). The data were analyzed with GeneMarker v. 1.85 (SoftGenetics, State College, Pennsylvania, USA). Data were normalized to reference probes and control samples. A deletion was defined as a peak ratio below 0.75; an amplification was defined as a peak ratio above 1.25.Array comparative genomic hybridization (Array-CGH) was performed using the human genome CGH Microarray 105K (Agilent Technologies, Santa Clara, California, USA) according to the manufacturer's protocol; data were analyzed with Genomic Workbench v. 5.0.14 (Agilent Technologies, Santa Clara, California, USA).Direct sequencing was used to analyze mutations or frameshif...

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Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity

2021

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Hematopoietic stem cells (HSCs) are the progenitor cells that give rise to the diverse repertoire of all immune cells. As they differentiate, HSCs yield a series of cell states that undergo gradual commitment to become mature blood cells. Studies of hematopoiesis in murine models have provided critical insights about the lineage relationships among stem cells, progenitors, and mature cells, and these have guided investigations of the molecular basis for these distinct developmental stages. Primary immune deficiencies are caused by inborn errors of immunity that result in immune dysfunction and subsequent susceptibility to severe and recurrent infection(s). Over the last decade there has been a dramatic increase in the number and depth of the molecular, cellular, and clinical characterization of such genetically defined causes of immune dysfunction. Patients harboring inborn errors of immunity thus represent a unique resource to improve our understanding of the multilayered and complex mechanisms underlying lymphocyte development in humans. These breakthrough discoveries not only enable significant advances in the diagnosis of such rare and complex conditions but also provide substantial improvement in the development of personalized treatments. Here, we will discuss the clinical, cellular, and molecular phenotypes, and treatments of selected inborn errors of immunity that impede, either intrinsically or extrinsically, the development of B-or T-cells at different stages.

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Ikaros limits basophil development by suppressing C/EBP-α expression

Abstract: Key Points Ik−/− mice overproduce basophils and their precursors in the absence of extrinsic inflammatory signals. Ikaros restrains development of basophils by regulating histone modifications at lineage-specifying genes, including Cebpa and Hes1.

Cited by 31 publications

References 61 publications

GATA2 is critical for the maintenance of cellular identity in differentiated mast cells derived from mouse bone marrow

GATA2 is critical for the maintenance of cellular identity in differentiated mast cells derived from mouse bone marrow

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity

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