Enhanced protein synthesis is a defining requirement for neonatal B cell development.

The LIN28B RNA binding protein exhibits an ontogenically restricted expression pattern and is a key molecular regulator of fetal and neonatal B lymphopoiesis. It enhances the positive selection of CD5+ immature B cells early in life through amplifying the CD19/PI3K/c-MYC pathway and is sufficient to reinitiate self-reactive B-1a cell output when ectopically expressed in the adult. In this study, interactome analysis in primary B cell precursors showed direct binding by LIN28B to numerous ribosomal protein transcripts, consistent with a regulatory role in cellular protein synthesis.

A self-sustaining layer of early-life-origin B cells drives steady-state IgA responses in the adult gut.

The adult immune system consists of cells that emerged at various times during ontogeny. We aimed to define the relationship between developmental origin and composition of the adult B cell pool during unperturbed hematopoiesis. Lineage tracing stratified murine adult B cells based on the timing of output, revealing that a substantial portion originated within a restricted neonatal window.

Lin28b controls a neonatal to adult switch in B cell positive selection.

The ability of B-1 cells to become positively selected into the mature B cell pool, despite being weakly self-reactive, has puzzled the field since its initial discovery. Here, we explore changes in B cell positive selection as a function of developmental time by exploiting a link between CD5 surface levels and the natural occurrence of self-reactive B cell receptors (BCRs) in BCR wild-type mice. We show that the heterochronic RNA binding protein Lin28b potentiates a neonatal mode of B cell selection characterized by enhanced overall positive selection in general and the developmental progression of CD5 immature B cells in particular.

Role of ZNF224 in c-Myc repression and imatinib responsiveness in chronic myeloid leukemia.

The transcription factor ZNF224 plays a key proapoptotic role in chronic myelogenous leukemia (CML), by modulating Wilms Tumor protein 1 (WT1) dependent apoptotic genes transcription. Recently, we demonstrated that Bcr-Abl signaling represses ZNF224 expression in Bcr-Abl positive CML cell lines and in CML patients. Interestingly, Imatinib and second-generation tyrosine kinase inhibitors specifically increase ZNF224 expression.

DNA and RNA binding by the Wilms' tumour gene 1 (WT1) protein +KTS and -KTS isoforms-From initial observations to recent global genomic analyses.

The Wilms' tumour gene 1 protein (WT1) is a zinc finger transcription factor found indispensable for foetal development. WT1 has also been implicated in the development of tumours in several organ systems, including acute myeloid leukaemia (AML). Four main WT1 isoforms come from 2 alternative splice events.

The transcriptional coregulator is a target gene for the Wilms' tumor gene 1 protein (WT1) in leukemic cells.

The Wilms' tumor gene 1 () is recurrently mutated in acute myeloid leukemia. Mutations and high expression of associate with a poor prognosis. In mice, WT1 cooperates with the () fusion gene in the induction of acute leukemia, further emphasizing a role for WT1 in leukemia development.

Anti-apoptotic quinolinate phosphoribosyltransferase (QPRT) is a target gene of Wilms' tumor gene 1 (WT1) protein in leukemic cells.

Wilms' tumor gene 1 (WT1) is a zinc finger transcription factor that has been implicated as an oncogene in leukemia and several other malignancies. When investigating possible gene expression network partners of WT1 in a large acute myeloid leukemia (AML) patient cohort, one of the genes with the highest correlation to WT1 was quinolinate phosphoribosyltransferase (QPRT), a key enzyme in the de novo nicotinamide adenine dinucleotide (NAD+) synthesis pathway. To investigate the possible relationship between WT1 and QPRT, we overexpressed WT1 in hematopoietic progenitor cells and cell lines, resulting in an increase of QPRT expression.

Distinct global binding patterns of the Wilms tumor gene 1 (WT1) -KTS and +KTS isoforms in leukemic cells.

The zinc finger transcription factor Wilms tumor gene 1 (WT1) acts as an oncogene in acute myeloid leukemia. A naturally occurring alternative splice event between zinc fingers three and four, removing or retaining three amino acids (±KTS), is believed to change the DNA binding affinity of WT1, although there are conflicting data regarding the binding affinity and motifs of the different isoforms. Increased expression of the WT1 -KTS isoform at the expense of the WT1 +KTS isoform is associated with poor prognosis in acute myeloid leukemia.

The hematopoietic tumor suppressor interferon regulatory factor 8 (IRF8) is upregulated by the antimetabolite cytarabine in leukemic cells involving the zinc finger protein ZNF224, acting as a cofactor of the Wilms' tumor gene 1 (WT1) protein.

The transcription factor interferon regulatory factor-8 (IRF8) is highly expressed in myeloid progenitors, while most myeloid leukemias show low or absent expression. Loss of IRF8 in mice leads to a myeloproliferative disorder, indicating a tumor-suppressive role of IRF8. The Wilms tumor gene 1 (WT1) protein represses the IRF8-promoter.

WT1-mediated repression of the proapoptotic transcription factor ZNF224 is triggered by the BCR-ABL oncogene.

The Kruppel-like protein ZNF224 is a co-factor of the Wilms' tumor 1 protein, WT1. We have previously shown that ZNF224 exerts a specific proapoptotic role in chronic myelogenous leukemia (CML) K562 cells and contributes to cytosine arabinoside-induced apoptosis, by modulating WT1-dependent transcription of apoptotic genes. Here we demonstrate that ZNF224 gene expression is down-regulated both in BCR-ABL positive cell lines and in primary CML samples and is restored after imatinib and second generation tyrosine kinase inhibitors treatment.

KAP1 is a Novel Substrate for the Arginine Methyltransferase PRMT5.

KRAB-associated protein 1 (KAP1), the transcriptional corepressor of Kruppel-associated box zinc finger proteins (KRAB-ZFPs), is subjected to multiple post-translational modifications that are involved in fine-tuning of the multiple biological functions of KAP1. In previous papers, we analyzed the KAP1-dependent molecular mechanism of transcriptional repression mediated by ZNF224, a member of the KRAB-ZFP family, and identified the protein arginine methyltransferase PRMT5 as a component of the ZNF224 repression complex. We demonstrated that PRMT5-mediated histone arginine methylation is required to elicit ZNF224 transcriptional repression.

KRAB-Zinc Finger Proteins: A Repressor Family Displaying Multiple Biological Functions.

Zinc finger proteins containing the Kruppel associated box (KRAB-ZFPs) constitute the largest individual family of transcriptional repressors encoded by the genomes of higher organisms. KRAB domain, positioned at the NH2 terminus of the KRAB-ZFPs, interacts with a scaffold protein, KAP-1, which is able to recruit various transcriptional factors causing repression of genes to which KRAB ZFPs bind. The relevance of such repression is reflected in the large number of the KRAB zinc finger protein genes in the human genome.

Role of WT1-ZNF224 interaction in the expression of apoptosis-regulating genes.

The transcription factor Wilms' tumor gene 1, WT1, is implicated both in normal developmental processes and in the generation of a variety of solid tumors and hematological malignancies. Physical interactions of other cellular proteins with WT1 are known to modulate its function. We previously identified the Krüppel-like zinc-finger protein, ZNF224, as a novel human WT1-associating protein that enhances the transcriptional activation of the human vitamin D receptor promoter by WT1.

ZNF224: Structure and role of a multifunctional KRAB-ZFP protein.

The Kruppel-like zinc finger protein ZNF224 was originally identified as the transcriptional repressor of the human aldolase A gene. ZNF224 transcriptional repression depends on interaction with the corepressor KAP-1 and the recruitment of enzyme activities modifying chromatin, in accordance with repression mechanism of KRAB-ZFP family. Recently, the arginine methyltransferase PRMT5 was demonstrated to play a crucial role in the transcriptional ZNF224 repressor complex.

Biochemical and functional interaction between ZNF224 and ZNF255, two members of the Kruppel-like zinc-finger protein family and WT1 protein isoforms.

Wilms' tumour suppressor gene, WT1, is mutated/deleted in approximately 15% of Wilms' tumours, highly expressed in the majority of other cancers and is essential for normal embryonic development. The gene encodes multiple isoforms of a zinc-finger (ZF) protein with diverse cellular functions, in particular participating in both transcriptional and post-transcriptional gene regulation. Physical interactions of other cellular proteins with WT1 are known to modulate its function.