Transcriptional dynamics in leukemia

  • Transcriptional dynamics in leukemia
Campus ICO-Germans Trias i Pujol

 

Josep Carreras Leukaemia Research Institute

Ctra de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona
Spain

Directions

Summary

The main interest of our lab is to understand the mechanisms that regulate transcription during normal and malignant haematopoiesis. We employ a combination of genome-wide techniques, genetic engineering tools and advanced microscopy imaging to reveal the genomic regulatory mechanisms that allow blood cells to integrate extracellular signalling information and implement new transcriptional programs. Our ultimate goal is to find molecular vulnerabilities that uncover new therapeutic strategies to treat myeloid malignancies.

Research

Hematopoietic differentiation is a tightly regulated process that ensures a constant flow of blood cell production throughout our lifetime. The transcriptional changes undergone by hematopoietic cells during differentiation are controlled at multiple levels, including transcription factor binding, chromatin modifications and the three-dimensional (3D) genome organization. Accurate integration of all these layers is essential to ensure production of sufficient numbers of blood cells at all stages of differentiation.

Mutations in genes encoding transcriptional regulators and chromatin modifiers are a major driver of acute myeloid leukemia (AML). The defective function of these mutant proteins alters the normal transcriptional dynamics and impairs normal differentiation, giving rise to the outgrowth of malignant clones. To understand how this occurs, we study the mechanisms that regulate transcription during hematopoietic differentiation and investigate the full spectrum of gene deregulation associated to recurrent AML mutations. More specifically, our main goals are:

  • To characterize and understand the main transcriptional and epigenetic events in Down syndrome leukemia. Acute megakaryoblastic leukemia is a pediatric leukemia with a strong incidence in children with trisomy 21. The most frequent genomic alterations include mutations in the transcription factor GATA1 and in three-dimensional genome organizer proteins such as cohesin or CTCF. We are investigating the precise role of these proteins in promoting this disease. 
  • To investigate the three-dimensional genomic landscape regulating Hox gene expression in normal and malignant haematopoiesis. Hox genes encode a large family of homeodomain-containing transcription factors that are essential for normal hematopoietic development. These genes are located in genomic clusters tightly regulated by specific enhancer elements. This accurate control is lost in many cases of AML and is thought to drive malignant clone expansion. We are characterizing the 3D conformation and enhancer landscape of Hox gene clusters in AML.
  • To understand the interplay between myeloid-specific mutations and alterations in signalling pathways commonly observed in myeloid malignancies. Inflammatory signals have a strong influence on blood development, and chronic inflammation has been associated to myeloid diseases such as Myelodysplastic Syndromes (MDS). We are investigating the impact of inflammation on the progression of myeloid malignancies and how they are linked to some of the most common epigenetic mutations.

 

Awards

La Caixa Junior Leader (2020)

People

Selected publications

Stik G, Vidal E, Barrero M, Cuartero S, Vila-Casadesús M, Mendieta-Esteban J, Tian TV, Choi J, Berenguer C, Abad A, Borsari B, le Dily F, Cramer P, Marti-Renom MA, Stadhouders R, Graf T

CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response.

Nat. Genet. 8 Jun 2020, . Epub 8 Jun 2020
Three-dimensional organization of the genome is important for transcriptional regulation
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Cuartero S, Innes AJ, Merkenschlager M

Towards a Better Understanding of Cohesin Mutations in AML.

Front Oncol 9 Sep 2019, 9 867.
Classical driver mutations in acute myeloid leukemia (AML) typically affect regulators of cell proliferation, differentiation, and survival. The selective advantage of increased proliferation, improved survival, and reduced differentiation on leukemia progression is immediately obvious. Recent large-scale sequencing efforts have uncovered numerous novel AML-associated mutations. Interestingly, a substantial fraction of the most frequently mutated genes encode general regulators of transcription and chromatin state. Understanding the selective advantage conferred by these mutations remains a major challenge. A striking example are mutations in genes of the cohesin complex, a major regulator of three-dimensional genome organization. Several landmark studies have shown that cohesin mutations perturb the balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPC). Emerging data now begin to uncover the molecular mechanisms that underpin this phenotype. Among these mechanisms is a role for cohesin in the control of inflammatory responses in HSPCs and myeloid cells. Inflammatory signals limit HSPC self-renewal and drive HSPC differentiation. Consistent with this, cohesin mutations promote resistance to inflammatory signals, and may provide a selective advantage for AML progression. In this review, we discuss recent progress in understanding cohesin mutations in AML, and speculate whether vulnerabilities associated with these mutations could be exploited therapeutically.
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Cuartero S, Weiss FD, Dharmalingam G, Guo Y, Ing-Simmons E, Masella S, Robles-Rebollo I, Xiao X, Wang YF, Barozzi I, Djeghloul D, Amano MT, Niskanen H, Petretto E, Dowell RD, Tachibana K, Kaikkonen MU, Nasmyth KA, Lenhard B, Natoli G, Fisher AG, Merkenschlager M

Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation.

Nat Immunol Sep 2018, 19 (9) 932-941. Epub 20 Aug 2018
Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that underpins inflammatory gene expression. Consistent with a role for inflammatory signals in promoting myeloid differentiation of hematopoietic stem and progenitor cells (HPSCs), cohesin mutations in HSPCs led to reduced inflammatory gene expression and increased resistance to differentiation-inducing inflammatory stimuli. These findings uncover an unexpected dependence of inducible gene expression on cohesin, link cohesin with myeloid differentiation, and may help explain the prevalence of cohesin mutations in human acute myeloid leukemia.
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Cuartero S, Merkenschlager M

Three-dimensional genome organization in normal and malignant haematopoiesis.

Curr Opin Hematol Jul 2018, 25 (4) 323-328.
The three-dimensional organization of the genome inside the nucleus impacts on key aspects of genome function, including transcription, DNA replication and repair. The chromosome maintenance complex cohesin and the DNA binding protein CTCF cooperate to drive the formation of self-interacting topological domains. This facilitates transcriptional regulation via enhancer-promoter interactions, controls the distribution and release of torsional strain, and affects the frequency with which particular translocations arise, based on the spatial proximity of translocation partners. Here we discuss recent insights into the mechanisms of three-dimensional genome organization, their relationship to haematopoietic differentiation and malignant transformation.
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Fresán U, Cuartero S, O'Connor MB, Espinàs ML

The insulator protein CTCF regulates Drosophila steroidogenesis.

Biol Open 15 May 2015, 4 (7) 852-7. Epub 15 May 2015
The steroid hormone ecdysone is a central regulator of insect development. In this report we show that CTCF expression in the prothoracic gland is required for full transcriptional activation of the Halloween genes spookier, shadow and noppera-bo, which encode ecdysone biosynthetic enzymes, and for proper timing of ecdysone-responsive gene expression. Loss of CTCF results in delayed and less synchronized larval development that can only be rescued by feeding larvae with both, the steroid hormone 20-hydroxyecdysone and cholesterol. Moreover, CTCF-knockdown in prothoracic gland cells leads to increased lipid accumulation. In conclusion, the insulator protein CTCF is required for Halloween gene expression and cholesterol homeostasis in ecdysone-producing cells controlling steroidogenesis.
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Cuartero S, Fresán U, Reina O, Planet E, Espinàs ML

Ibf1 and Ibf2 are novel CP190-interacting proteins required for insulator function.

EMBO J 18 Mar 2014, 33 (6) 637-47. Epub 6 Feb 2014
Insulators are DNA-protein complexes that play a central role in chromatin organization and regulation of gene expression. In Drosophila different proteins, dCTCF, Su(Hw), and BEAF bind to specific subsets of insulators most of them having in common CP190. It has been shown that there are a number of CP190-binding sites that are not shared with any other known insulator protein, suggesting that other proteins could cooperate with CP190 to regulate insulator activity. Here we report on the identification of two previously uncharacterized proteins as CP190-interacting proteins, that we have named Ibf1 and Ibf2. These proteins localize at insulator bodies and associate with chromatin at CP190-binding sites throughout the genome. We also show that Ibf1 and Ibf2 are DNA-binding proteins that form hetero-oligomers that mediate CP190 binding to chromatin. Moreover, Ibf1 and Ibf2 are necessary for insulator activity in enhancer-blocking assays and Ibf2 null mutation cause a homeotic phenotype. Taken together our data reveal a novel pathway of CP190 recruitment to chromatin that is required for insulator activity.
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