CBFβ-MYH11 interferes with megakaryocyte differentiation via modulating a gene program that includes GATA2 and KLF1

Yi, Guoqiang; Mandoli, Amit; Jussen, Laura; Tijchon, Esther; Bergen, Maaike G.J.M. van; Cordonnier, Gaëlle; Hansen, Marten; Kim, Bowon; Nguyen, Luan N.; Jansen, Pascal W.T.C.; Vermeulen, Michiel; Reijden, Bert van der; Akker, Emile van den; Bond, Jonathan; Martens, Joost H.A.

doi:10.1038/s41408-019-0194-8

Cited by 11 publications

(8 citation statements)

References 43 publications

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“…ERG knockdown reduced ME-1 colony formation in methylcellulose (Figure S8E), consistent with a shift away from the HSC-like state. We also analysed RNAseq data from GATA2 over-expression in ME-1 cells 63 and found that increased GATA2 led to increased TAL1 and RUNX1, and reduced ERG and LMO2, similar to expression changes between Ery-precursor-like and HSC-like ME-1 cells (Figure 5C, left, compare to Figure 4F, left). GSEA analysis was used to compare GATA2 driven changes in global gene expression to expression differences between Ery-precursors and HSCs.…”

Section: Direct Manipulation Of Gata2 and Erg Promotes Erythroid Traj...mentioning

confidence: 68%

Disruption of a GATA2-TAL1-ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells

Thoms

Truong

Subramanian

et al. 2021

Blood

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Changes in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These transitions are disrupted during leukemic transformation but knowledge of the gene regulatory changes underpinning this process is elusive. We hypothesised that identifying core gene regulatory networks in healthy hematopoietic and leukemic cells could provide insights into network alterations that perturb cell state transitions. A heptad of transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, RUNX1) bind key hematopoietic genes in human CD34+ haematopoietic stem and progenitor cells (HSPCs) and have prognostic significance in acute myeloid leukemia (AML). These factors also form a densely interconnected circuit by binding combinatorially at their own, and each other's, regulatory elements. However, their mutual regulation during normal haematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. Here, we integrated bulk and single cell data and found that the fully connected heptad circuit identified in healthy HSPCs persists with only minor alterations in AML, and that chromatin accessibility at key heptad regulatory elements was predictive of cell identity in both healthy progenitors and in leukemic cells. The heptad factors GATA2, TAL1 and ERG formed an integrated sub-circuit that regulates stem cell to erythroid transition in both healthy and leukemic cells. Components of this triad could be manipulated to facilitate erythroid transition providing a proof of concept that such regulatory circuits could be harnessed to promote specific cell type transitions and overcome dysregulated haematopoiesis.

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Section: Direct Manipulation Of Gata2 and Erg Promotes Erythroid Traj...mentioning

confidence: 68%

Disruption of a GATA2-TAL1-ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells

Thoms

Truong

Subramanian

et al. 2021

Blood

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“…On the other hand, the aberrant activation of KLF1 and TAL1 may illustrate an oncogenic function of IRX1 in megakaryoblastic AML. The CBFb-MYH11 fusion gene reportedly deregulates the activity of GATA2 and KLF1, and thus inhibits megakaryopoiesis and erythropoiesis [ 63 ]. Here, while excluding the presence of CBFb-MYH11 fusion, we detected the aberrant activity of IRX3/IRX5, an alternative mechanism to perturb myeloid differentiation via KLF1 deregulation.…”

Section: Discussionmentioning

confidence: 99%

The Hematopoietic TALE-Code Shows Normal Activity of IRX1 in Myeloid Progenitors and Reveals Ectopic Expression of IRX3 and IRX5 in Acute Myeloid Leukemia

Nagel

Pommerenke

Meyer

et al. 2022

IJMS

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Homeobox genes encode transcription factors that control basic developmental decisions. Knowledge of their hematopoietic activities casts light on normal and malignant immune cell development. Recently, we constructed the so-called lymphoid TALE-code that codifies expression patterns of all active TALE class homeobox genes in early hematopoiesis and lymphopoiesis. Here, we present the corresponding myeloid TALE-code to extend this gene signature, covering the entire hematopoietic system. The collective data showed expression patterns for eleven TALE homeobox genes and highlighted the exclusive expression of IRX1 in megakaryocyte-erythroid progenitors (MEPs), implicating this TALE class member in a specific myeloid differentiation process. Analysis of public profiling data from acute myeloid leukemia (AML) patients revealed aberrant activity of IRX1 in addition to IRX3 and IRX5, indicating an oncogenic role for these TALE homeobox genes when deregulated. Screening of RNA-seq data from 100 leukemia/lymphoma cell lines showed overexpression of IRX1, IRX3, and IRX5 in megakaryoblastic and myelomonocytic AML cell lines, chosen as suitable models for studying the regulation and function of these homeo-oncogenes. Genomic copy number analysis of IRX-positive cell lines demonstrated chromosomal amplification of the neighboring IRX3 and IRX5 genes at position 16q12 in MEGAL, underlying their overexpression in this cell line model. Comparative gene expression analysis of these cell lines revealed candidate upstream factors and target genes, namely the co-expression of GATA1 and GATA2 together with IRX1, and of BMP2 and HOXA10 with IRX3/IRX5. Subsequent knockdown and stimulation experiments in AML cell lines confirmed their activating impact in the corresponding IRX gene expression. Furthermore, we demonstrated that IRX1 activated KLF1 and TAL1, while IRX3 inhibited GATA1, GATA2, and FST. Accordingly, we propose that these regulatory relationships may represent major physiological and oncogenic activities of IRX factors in normal and malignant myeloid differentiation, respectively. Finally, the established myeloid TALE-code is a useful tool for evaluating TALE homeobox gene activities in AML.

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“…Since the bulk of ME-1 cells were assigned as HSC-like, we reasoned that increased expression of GATA2 might alter their trajectory towards the Ery-precursor-like state. We analysed RNAseq data from GATA2 over-expression in ME-1 cells 61 and found that increased GATA2 led to increased TAL1 and RUNX1, and reduced ERG and LMO2, similar to expression changes between Ery-precursor-like and HSC-like ME-1 cells( Figure 5C, left, compare to Figure 4F, left). GSEA analysis was used to compare GATA2 driven changes in global gene expression to expression differences between Ery-precursors and HSCs.…”

Section: Direct Manipulation Of Gata2 and Erg Promotes Erythroid Trajmentioning

confidence: 65%

Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells

Thoms

Knezevic

Harvey

et al. 2020

Preprint

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Changes in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These transitions are disrupted during leukemic transformation but knowledge of the gene regulatory changes underpinning this process is elusive. We hypothesised that identifying core gene regulatory networks in healthy hematopoietic and leukemic cells could provide insights into network alterations that perturb cell state transitions. A heptad of transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, RUNX1) bind key hematopoietic genes in human CD34+ haematopoietic stem and progenitor cells (HSPCs) and have prognostic significance in acute myeloid leukemia (AML). These factors also form a densely interconnected circuit by binding combinatorially at their own, and each other′s, regulatory elements. However, their mutual regulation during normal haematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. Here, we integrated bulk and single cell data and found that the fully connected heptad circuit identified in healthy HSPCs persists with only minor alterations in AML, and that chromatin accessibility at key heptad regulatory elements was predictive of cell identity in both healthy progenitors and in leukemic cells. The heptad factors GATA2, TAL1 and ERG formed an integrated sub-circuit that regulates stem cell to erythroid transition in both healthy and leukemic cells. Components of this triad could be manipulated to facilitate erythroid transition providing a proof of concept that such regulatory circuits could be harnessed to promote specific cell type transitions and overcome dysregulated haematopoiesis.

show abstract

CBFβ-MYH11 interferes with megakaryocyte differentiation via modulating a gene program that includes GATA2 and KLF1

Cited by 11 publications

References 43 publications

Disruption of a GATA2-TAL1-ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells

Disruption of a GATA2-TAL1-ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells

The Hematopoietic TALE-Code Shows Normal Activity of IRX1 in Myeloid Progenitors and Reveals Ectopic Expression of IRX3 and IRX5 in Acute Myeloid Leukemia

Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells

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