Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia

Almotiri, Alhomidi; Alzahrani, Hamed Ahmad A.; Menendez-Gonzalez, Juan Bautista; Abdelfattah, Ali; Alotaibi, Badi; Saleh, Lubaid; Greene, Adelle; Georgiou, Mia R. F.; Gibbs, Alex; Alsayari, Amani Salem; Taha, Sarab; Thomas, Leigh-anne; Shah, Dhruv; Edkins, Sarah; Giles, Peter; Stemmler, Marc P.; Brabletz, Simone; Brabletz, Thomas; Boyd, Ashleigh S.; Siebzehnrübl, Florian A.; Rodrigues, Neil P.

doi:10.1172/jci129115

Cited by 46 publications

(61 citation statements)

References 97 publications

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“…During the final preparation of this manuscript, Almotiri and colleagues published a similar study [ 63 ] as ours using the same conditional Zeb1 allele that we have used in this study [ 24 ]. However, their analysis of ZEB1 predominantly used the inducible Mx1-Cre mouse model to delete Zeb1 alone, whereas this study predominantly used constitutive hematopoietic enhanced Tie2 and restricted Vav-iCre lines with BM transplants to determine the cell-autonomous role of Zeb1 in hematopoiesis.…”

Section: Discussionmentioning

confidence: 99%

“…Adult mice develop myeloproliferative disease over time that is driven by enhanced G-CSF responsiveness [9] as well as mild differentiation defects in multiple HSPC populations including increased LT-HSCs, increased MEPs, decreased GMPs as well as defects in mature hematopoietic populations including decreased RBC, megakaryocytes, monocytes, and B cells but expanded terminal granulocyte differentiation (red arrows). (C) Represents a hybrid summary view between results of this study (red arrows) along with those found by [63] (blue arrows). Unlike Zeb2 KOs LSK, ST-HSC and MPP numbers are down in Zeb1 hematopoietic null mice and display multilineage differentiation defects with decreased numbers of progenitors and mature hematopoietic cells particularly T cells with mice developing thymic atrophy [62].…”

Section: Plos Biologymentioning

confidence: 93%

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Interplay between the EMT transcription factors ZEB1 and ZEB2 regulates hematopoietic stem and progenitor cell differentiation and hematopoietic lineage fidelity

et al. 2021

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The ZEB2 transcription factor has been demonstrated to play important roles in hematopoiesis and leukemic transformation. ZEB1 is a close family member of ZEB2 but has remained more enigmatic concerning its roles in hematopoiesis. Here, we show using conditional loss-of-function approaches and bone marrow (BM) reconstitution experiments that ZEB1 plays a cell-autonomous role in hematopoietic lineage differentiation, particularly as a positive regulator of monocyte development in addition to its previously reported important role in T-cell differentiation. Analysis of existing single-cell (sc) RNA sequencing (RNA-seq) data of early hematopoiesis has revealed distinctive expression differences between Zeb1 and Zeb2 in hematopoietic stem and progenitor cell (HSPC) differentiation, with Zeb2 being more highly and broadly expressed than Zeb1 except at a key transition point (short-term HSC [ST-HSC]➔MPP1), whereby Zeb1 appears to be the dominantly expressed family member. Inducible genetic inactivation of both Zeb1 and Zeb2 using a tamoxifen-inducible Cre-mediated approach leads to acute BM failure at this transition point with increased long-term and short-term hematopoietic stem cell numbers and an accompanying decrease in all hematopoietic lineage differentiation. Bioinformatics analysis of RNA-seq data has revealed that ZEB2 acts predominantly as a transcriptional repressor involved in restraining mature hematopoietic lineage gene expression programs from being expressed too early in HSPCs. ZEB1 appears to fine-tune this repressive role during hematopoiesis to ensure hematopoietic lineage fidelity. Analysis of Rosa26 locus–based transgenic models has revealed that Zeb1 as well as Zeb2 cDNA-based overexpression within the hematopoietic system can drive extramedullary hematopoiesis/splenomegaly and enhance monocyte development. Finally, inactivation of Zeb2 alone or Zeb1/2 together was found to enhance survival in secondary MLL-AF9 acute myeloid leukemia (AML) models attesting to the oncogenic role of ZEB1/2 in AML.

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Section: Discussionmentioning

confidence: 99%

Section: Plos Biologymentioning

confidence: 93%

Interplay between the EMT transcription factors ZEB1 and ZEB2 regulates hematopoietic stem and progenitor cell differentiation and hematopoietic lineage fidelity

et al. 2021

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“…We have shown that ZNF521 interacts with the NuRD complex for transcriptional repression [ 30 , 51 ]. Recently, there have been two manuscripts delineating the role for ZEB1 in HSCs and their differentiation using models with Zeb1 −/− , where there was an acceleration of MLL-AF9 and Meis1a/Hoxa9-driven AML progression, implicating Zeb1 as a tumor suppressor in AML LSCs [ 52 ]. In AML with a high expression of ZEB1, AML is closely correlated with poor patient prognosis, and mechanistically, it was found that ZEB1 can interact with P53 and can regulate the PTEN/PI3K/AKT signaling pathway [ 53 ].…”

Section: Resultsmentioning

confidence: 99%

ZNF521 Enhances MLL-AF9-Dependent Hematopoietic Stem Cell Transformation in Acute Myeloid Leukemias by Altering the Gene Expression Landscape

Chiarella

Aloisio

Scicchitano

et al. 2021

IJMS

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Leukemias derived from the MLL-AF9 rearrangement rely on dysfunctional transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. Here, we demonstrate that ZNF521 mRNA levels correlate with specific genetic aberrations: in particular, the highest expression is observed in AMLs bearing MLL rearrangements, while the lowest is detected in AMLs with FLT3-ITD, NPM1, or CEBPα double mutations. In cord blood-derived CD34+ cells, enforced expression of ZNF521 provides a significant proliferative advantage and enhances MLL-AF9 effects on the induction of proliferation and the expansion of leukemic progenitor cells. Transcriptome analysis of primary CD34+ cultures displayed subsets of genes up-regulated by MLL-AF9 or ZNF521 single transgene overexpression as well as in MLL-AF9/ZNF521 combinations, at either the early or late time points of an in vitro leukemogenesis model. The silencing of ZNF521 in the MLL-AF9 + THP-1 cell line coherently results in an impairment of growth and clonogenicity, recapitulating the effects observed in primary cells. Taken together, these results underscore a role for ZNF521 in sustaining the self-renewal of the immature AML compartment, most likely through the perturbation of the gene expression landscape, which ultimately favors the expansion of MLL-AF9-transformed leukemic clones.

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“…However, previous research reported that BAMBI, a tumor suppressor, was modified by H3K27ac [24]. ZEB1 has tumor suppressor activity and is down-regulated in tumors, while H3K4me3 is also enriched in the promoter region of ZEB1 [25,26]. The mechanism of gene transcription and expression is complex and affected by many factors, including DNA methylation and histone modification.…”

Section: Discussionmentioning

confidence: 98%

Epigenetic modifications inhibit the expression of MARVELD1 and in turn tumorigenesis by regulating the Wnt/β-catenin pathway in pan-cancer

Zhang¹,

Li²,

Sun³

et al. 2022

J. Cancer

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MARVEL domain-containing 1 (MARVELD1) is one of the MARVEL domain-containing proteins. Expression of MARVELD1 in tumor and non-tumor tissues, the relationship between its expression and cancer prognosis, and upstream regulation of MARVELD1 were examined using pan-cancer data from The Cancer Genome Atlas. MARVELD1 expression was significantly downregulated in tissues used for pan-cancer analysis compared to that in normal tissues. Low expression of MARVELD1 was associated with poor disease outcomes in pan-cancer. Colon cancer patients with low expression of MARVELD1 had worse progression free survival and overall survival than those with high expression levels in our cohort. Hypermethylation and histone modification in the MARVELD1 promoter locus synergistically affected its expression in pan-cancer. The function of MARVELD1 in colon cancer remains to be studied. Gene Ontology enrichment analysis revealed that MARVELD1 may modulate processes associated with inhibition of tumorigenesis in colon cancer. Both upstream transcription factors and downstream functional enrichment of MARVELD1 were related to the Wnt/β-catenin signaling pathway. Overexpression of MARVELD1 inhibited the expression of β-catenin and its entry into the nucleus. MARVELD1 also inhibited the proliferation, migration, and invasion of colon cancer cells. With Wnt/β-catenin activator LiCl treatment, rescue experiments demonstrated that the role of MARVELD1 in colon cancer progression was dependent on the Wnt/β-catenin pathway. These results indicate that MARVELD1 acts as a tumor suppressor and inhibits tumorigenesis via the Wnt/β-catenin pathway.

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Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia

Cited by 46 publications

References 97 publications

Interplay between the EMT transcription factors ZEB1 and ZEB2 regulates hematopoietic stem and progenitor cell differentiation and hematopoietic lineage fidelity

Interplay between the EMT transcription factors ZEB1 and ZEB2 regulates hematopoietic stem and progenitor cell differentiation and hematopoietic lineage fidelity

ZNF521 Enhances MLL-AF9-Dependent Hematopoietic Stem Cell Transformation in Acute Myeloid Leukemias by Altering the Gene Expression Landscape

Epigenetic modifications inhibit the expression of MARVELD1 and in turn tumorigenesis by regulating the Wnt/β-catenin pathway in pan-cancer

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