Dinàmica transcripcional de la Leucèmia

  • Cuartero Lab 2022
ICO - German 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

2020  La Caixa Junior Leader

2022 ASH Global Research Award

2022 Ramón y Cajal 

People

Selected publications

Cuartero S, Stik G, Stadhouders R

Three-dimensional genome organization in immune cell fate and function.

Nat Rev Immunol 20 Set 2022, . Epub 20 Set 2022
Immune cell development and activation demand the precise and coordinated control of transcriptional programmes. Three-dimensional (3D) organization of the genome has emerged as an important regulator of chromatin state, transcriptional activity and cell identity by facilitating or impeding long-range genomic interactions among regulatory elements and genes. Chromatin folding thus enables cell type-specific and stimulus-specific transcriptional responses to extracellular signals, which are essential for the control of immune cell fate, for inflammatory responses and for generating a diverse repertoire of antigen receptor specificities. Here, we review recent findings connecting 3D genome organization to the control of immune cell differentiation and function, and discuss how alterations in genome folding may lead to immune dysfunction and malignancy.
Més informació
Robles-Rebollo I, Cuartero S, Canellas-Socias A, Wells S, Karimi MM, Mereu E, Chivu AG, Heyn H, Whilding C, Dormann D, Marguerat S, Rioja I, Prinjha RK, Stumpf MPH, Fisher AG, Merkenschlager M

Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters.

Nat Commun 27 Jul 2022, 13 (1) 4342. Epub 27 Jul 2022
Innate immune responses rely on inducible gene expression programmes which, in contrast to steady-state transcription, are highly dependent on cohesin. Here we address transcriptional parameters underlying this cohesin-dependence by single-molecule RNA-FISH and single-cell RNA-sequencing. We show that inducible innate immune genes are regulated predominantly by an increase in the probability of active transcription, and that probabilities of enhancer and promoter transcription are coordinated. Cohesin has no major impact on the fraction of transcribed inducible enhancers, or the number of mature mRNAs produced per transcribing cell. Cohesin is, however, required for coupling the probabilities of enhancer and promoter transcription. Enhancer-promoter coupling may not be explained by spatial proximity alone, and at the model locus Il12b can be disrupted by selective inhibition of the cohesinopathy-associated BET bromodomain BD2. Our data identify discrete steps in enhancer-mediated inducible gene expression that differ in cohesin-dependence, and suggest that cohesin and BD2 may act on shared pathways.
Més informació
de Castro CPM, Cadefau M, Cuartero S

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome.

Cancers (Basel) 18 Ago 2021, 13 (16) . Epub 18 Ago 2021
Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators-such as cohesin,
Més informació
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
Més informació
Cuartero S, Innes AJ, Merkenschlager M

Towards a Better Understanding of Cohesin Mutations in AML.

Front Oncol 9 Set 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.
Més informació
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 Set 2018, 19 (9) 932-941. Epub 20 Ago 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.
Més informació
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