Regulation of hematopoietic development by ZBTB transcription factors

Maeda, Takahiro

doi:10.1007/s12185-016-2035-x

Cited by 73 publications

(64 citation statements)

References 178 publications

(258 reference statements)

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“…Th-POK and BCL6 are master regulators of Th and TFH lineage commitment, respectively ( 5 , 8 , 9 ), both of which belong to the poxvirus and zinc finger (POZ) and Krüppel-type (POK) protein family. POK family members often act as oncogenes in various hematological malignancies ( 27 ). For example, chromosomal translocation involving PLZF [t(11 ; 17) (q23 ; q21), PLZF / RARα and RARα / PLZF ] is associated with acute promyelocytic leukemia ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Expression of Master Regulators of T-cell, Helper T-cell and Follicular Helper T-cell Differentiation in Angioimmunoblastic T-cell Lymphoma

Matsumoto¹,

Nagoshi

Yoshida³

et al. 2017

Intern. Med.

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Objective It has been postulated that the normal counterpart of angioimmunoblastic T-cell lymphoma (AITL) is the follicular helper T-cell (TFH). Recent immunological studies have identified several transcription factors responsible for T-cell differentiation. The master regulators associated with T-cell, helper T-cell (Th), and TFH differentiation are reportedly BCL11B, Th-POK, and BCL6, respectively. We explored the postulated normal counterpart of AITL with respect to the expression of the master regulators of T-cell differentiation. Methods We performed an immunohistochemical analysis in 15 AITL patients to determine the expression of the master regulators and several surface markers associated with T-cell differentiation. Results BCL11B was detected in 10 patients (67%), and the surface marker of T-cells (CD3) was detected in all patients. Only 2 patients (13%) expressed the marker of naïve T-cells (CD45RA), but all patients expressed the marker of effector T-cells (CD45RO). Nine patients expressed Th-POK (60%), and 7 (47%) expressed a set of surface antigens of Th (CD4-positive and CD8-negative). In addition, BCL6 and the surface markers of TFH (CXCL13, PD-1, and SAP) were detected in 11 (73%), 8 (53%), 14 (93%), and all patients, respectively. Th-POK-positive/BCL6-negative patients showed a significantly shorter overall survival (OS) than the other patients (median OS: 33.0 months vs. 74.0 months, p=0.020; log-rank test). Conclusion Many of the AITL patients analyzed in this study expressed the master regulators of T-cell differentiation. The clarification of the diagnostic significance and pathophysiology based on the expression of these master regulators in AITL is expected in the future.

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Section: Discussionmentioning

confidence: 99%

Expression of Master Regulators of T-cell, Helper T-cell and Follicular Helper T-cell Differentiation in Angioimmunoblastic T-cell Lymphoma

Matsumoto¹,

Nagoshi

Yoshida³

et al. 2017

Intern. Med.

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“…The predicted chimeric protein contains one dimerizing BTB/POZ domain and one zinc-finger-C2H2 domain of ZBTB20 at the amino terminus fused with the JAK2-tyrosine-kinase domain ( Fig. 2E), allowing for constitutive activation of ZBTB20-JAK2 fusion protein through partner-mediated oligomerization, similar to other known kinase-activating JAK2 gene fusions (Roberts et al 2014;Maeda 2016;Zhu et al 2018). Furthermore, the cytogenomic array identified a deep 107-kB deletion at Chromosome 7p12, consistent with a homozygous IKZF1 deletion (data not shown).…”

Section: Genomic Analysismentioning

confidence: 88%

“…ZBTB20-JAK2 gene fusion in myeloid/lymphoid neoplasm with eosinophilia presenting as B-ALL An in-frame fusion between ZBTB20 exon 4 as the 5 ′ partner (ZBTB20:NM_00116342 [exon:4] Chr 3:114069121) and JAK2 exon19 as the 3 ′ partner (JAK2:NM_004972 [exon:19] Chr 9:5081725) was identified using the Archer next-generation sequencing (NGS) assay and analysis based on human genome assembly version hg19 (see Table 1) . ZBTB20 is reportedly expressed in germinal center B cells, plasma cells, and neuronal tissues, but the expression in myeloid/erythroid precursors remains unknown (Chevrier et al 2014;Wang and Bhattacharya 2014;Maeda 2016;Zhu et al 2018). Expression of ZBTB20-JAK2 RNA chimeric transcripts was confirmed by Sanger sequencing on cDNA amplicons (Fig.…”

Section: Genomic Analysismentioning

confidence: 88%

The diagnostic challenges and clinical course of a myeloid/lymphoid neoplasm with eosinophilia and ZBTB20-JAK2 gene fusion presenting as B-lymphoblastic leukemia

Lee

Pfau

Choi

et al. 2020

Cold Spring Harb Mol Case Stud

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We report the diagnostic challenges and the clinical course of a patient with an extraordinary presentation of B-lymphoblastic leukemia (B-ALL) with eosinophilia. We identified a novel ZBTB20-JAK2 gene fusion as a chimeric RNA transcript using the Archer platform. This gene fusion from the same patient was recently identified by Peterson et al. (2019) at the genomic level using a different sequencing technology platform. The configuration of this gene fusion predicts the production of a kinase-activating JAK2 fusion protein, which would normally lead to a diagnosis of Philadelphia chromosome-like BALL (Ph-like BALL). However, the unusual presentation of eosinophilia led us to demonstrate the presence of this gene fusion in nonlymphoid hematopoietic cells by fluorescence in situ hybridization (FISH) studies with morphologic correlation. Therefore, we believe this disease, in fact, represents blast crisis arising from an underlying myeloid neoplasm with JAK2 rearrangements. This case illustrates the difficulty in differentiating Ph-like BALL and myeloid/lymphoid neoplasm with eosinophilia and gene rearrangements (MLN-EGR) in blast crisis. As currently defined, the diagnosis of MLN-EGR relies on the hematologic presentations and the identification of marker gene fusions (including PCM1-JAK2, ETV6-JAK2, and BCR-JAK2). However, these same gene fusions, when limited to B-lymphoblasts, also define Ph-like BALL. Yet, our case does not conform to either condition. Therefore, the assessment for lineage restriction of gene rearrangements to reflect the pathophysiologic difference between BALL and MLN-EGR in blast crisis is likely a more robust diagnostic approach and allows the inclusion of MLN-EGR with novel gene fusions.

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“…Another exciting target would be ZBTB7A given its potent role in HbF repression. However ZBTB7A is required for terminal erythropoiesis and germinal center B cell maturation and plays important roles in Tlymphocytes, osteoclasts and HSCs 28 . A specific NuRD subcomplex including CHD4, GATAD2A, MBD2, MTA2 and HDAC2 is required for HbF silencing 6,29 .…”

Section: Discussionmentioning

confidence: 99%

ZNF410 represses fetal globin by devoted control of CHD4/NuRD

Vinjamur¹,

Yao²,

Cole³

et al. 2020

Preprint

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Major effectors of adult-stage fetal globin silencing include the transcription factors (TFs) BCL11A and ZBTB7A/LRF and the NuRD chromatin complex, although each has potential on-target liabilities for rational β-hemoglobinopathy therapeutic inhibition. Here through CRISPR screening we discover ZNF410 to be a novel fetal hemoglobin (HbF) repressing TF. ZNF410 does not bind directly to the γ-globin genes but rather its chromatin occupancy is solely concentrated at CHD4, encoding the NuRD nucleosome remodeler, itself required for HbF repression. CHD4 has two ZNF410-bound regulatory elements with 27 combined ZNF410 binding motifs constituting unparalleled genomic clusters. These elements completely account for ZNF410’s effects on γ-globin repression. Knockout of ZNF410 reduces CHD4 by 60%, enough to substantially de-repress HbF while avoiding the cellular toxicity of complete CHD4 loss. Mice with constitutive deficiency of the homolog Zfp410 are born at expected Mendelian ratios with unremarkable hematology. ZNF410 is dispensable for human hematopoietic engraftment potential and erythroid maturation unlike known HbF repressors. These studies identify a new rational target for HbF induction for the β-hemoglobin disorders with a wide therapeutic index. More broadly, ZNF410 represents a special class of gene regulator, a conserved transcription factor with singular devotion to regulation of a chromatin subcomplex.

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Regulation of hematopoietic development by ZBTB transcription factors

Cited by 73 publications

References 178 publications

Expression of Master Regulators of T-cell, Helper T-cell and Follicular Helper T-cell Differentiation in Angioimmunoblastic T-cell Lymphoma

Expression of Master Regulators of T-cell, Helper T-cell and Follicular Helper T-cell Differentiation in Angioimmunoblastic T-cell Lymphoma

The diagnostic challenges and clinical course of a myeloid/lymphoid neoplasm with eosinophilia and ZBTB20-JAK2 gene fusion presenting as B-lymphoblastic leukemia

ZNF410 represses fetal globin by devoted control of CHD4/NuRD

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