Iman Fares - Academia.edu (original) (raw)

Papers by Iman Fares

Research paper thumbnail of MYCT1 Controls Environmental Sensing to Maintain Self-Renewal in Human Hematopoietic Stem Cells

Research paper thumbnail of S248: The Endosomal Adaptor Protein MYCT1 Controls Environmental Sensing in Human HSCS

Research paper thumbnail of Supplementary Figure from <i>BCOR</i> and <i>BCORL1</i> Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Research paper thumbnail of Supplementary Data from <i>BCOR</i> and <i>BCORL1</i> Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Supplementary Data from BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Si... more Supplementary Data from BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Research paper thumbnail of 2009 – the Endosomal Adaptor Protein MYCT1 Controls Human Hematopoietic Stem Cell Function

Experimental Hematology, Aug 1, 2021

Research paper thumbnail of Data from <i>BCOR</i> and <i>BCORL1</i> Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb ... more Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well-defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1-mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1 tumor-suppressive activity and identifies a therapeutic strategy in PRC1.1-mutated cancer.Significance:We demonstrate that BCOR and BCORL1 mutations in leukemia unlink PRC1.1 repressive function from target genes, resulting in epigenetic reprogramming and activation of aberrant cell signaling programs that mediate treatment resistance. Our study provides mechanistic insights into the pathogenesis of PRC1.1-mutated leukemia that inform novel therapeutic approaches.This article is highlighted in the In This Issue feature, p. 85

Research paper thumbnail of 3016 – MYCT1 Controls Human Hematopoietic Stem Cell Function by Moderating Endocytosis and Environmental Sensing

Research paper thumbnail of Supplementary Data from BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Supplementary Data from BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Si... more Supplementary Data from BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Research paper thumbnail of Data from BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb ... more Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well-defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1-mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1...

Research paper thumbnail of 2001 – the Endosomal Adaptor Protein MYCT1 Controls Environmental Sensing in Human Hematopoietic Stem Cells

Research paper thumbnail of 2023 – Two Distinct Isoforms of MLLT3 Balance Human HSC Fate Decisions

Research paper thumbnail of 2009 – the Endosomal Adaptor Protein MYCT1 Controls Human Hematopoietic Stem Cell Function

Research paper thumbnail of 2001 – the Endosomal Adaptor Protein MYCT1 Controls Environmental Sensing in Human Hematopoietic Stem Cells

Experimental Hematology, 2022

Research paper thumbnail of 3163 – Modulation of Rna Polymerase II Activity Regulates Human HSC Self-Renewal

Research paper thumbnail of 3037 – Two Distinct Isoforms of MLLT3 Regulate Human HSC Function

Research paper thumbnail of Mapping human haematopoietic stem cells from haemogenic endothelium to birth

Nature

Human hematopoietic stem cell (HSC) ontogeny is poorly defined due to the inability to identify H... more Human hematopoietic stem cell (HSC) ontogeny is poorly defined due to the inability to identify HSCs as they emerge and mature in different hematopoietic sites. We created a single-cell transcriptome map of human hematopoietic tissues from 1 st trimester to birth and found that HSC signature RUNX1+HOXA9+MLLT3+MECOM+HLF+SPINK2+ distinguishes HSCs from progenitors throughout gestation. In addition to the AGM (aorta-gonad-mesonephros) region, nascent HSCs populated the placenta and yolk sac before colonizing the liver at 6 weeks. Comparison of HSCs from different maturation stages revealed the establishment of HSC transcription factor machinery upon HSC emergence, whereas their surface phenotype evolved throughout development. HSC transition to the liver marked a molecular shift evidenced by suppression of surface antigens, reflecting nascent HSC identity, and acquisition of HSC maturity markers PROM1/CD133 and HLA-DR. HSC origin was tracked to ALDH1A1+KCNK17+ hemogenic endothelial (HE) cells, which arose from IL33+ALDH1A1+ arterial endothelial subset, termed pre-HE. Spatial transcriptomics and immunofluorescence visualized this process in ventrally located intra-aortic hematopoietic clusters. The in vivo map of human HSC ontogeny validated the generation of AGM-like definitive HSPCs from human pluripotent stem cells, and serves as a guide to improve their maturation to functional HSCs.

Research paper thumbnail of Decoding Human Hematopoietic Stem Cell Self-Renewal

Current Stem Cell Reports

Purpose of Review Hematopoietic stem cells (HSCs) maintain blood and immune cell homeostasis by b... more Purpose of Review Hematopoietic stem cells (HSCs) maintain blood and immune cell homeostasis by balancing quiescence, self-renewal, and differentiation. HSCs can be used in lifesaving transplantation treatments to create a healthy hematopoietic system in patients suffering from malignant or inherited blood diseases. However, lack of matching bone marrow donors, and the low quantity of HSCs in a single cord blood graft, are limitations for successful transplantation. The enormous regenerative potential of HSCs has raised the hope that HSC self-renewal could be recapitulated in culture to achieve robust expansion of HSCs for therapeutic use. Yet, when HSCs are cultured ex vivo their function becomes compromised, limiting successful expansion. Recent Findings After decades of efforts to expand human HSCs ex vivo that resulted in minimal increase in transplantable units, recent studies have helped define culture conditions that can increase functional HSCs. These studies have provided n...

Research paper thumbnail of BCOR and BCORL1 mutations drive epigenetic reprogramming and oncogenic signaling by unlinking PRC1.1 from target genes

Research paper thumbnail of BCOR and BCORL1 mutations disrupt PRC1.1 repressive function in leukemia by unlinking the RING-PCGF1 enzymatic core from target genes

bioRxiv, 2021

BCOR and its paralog BCORL1 encode subunits of the Polycomb repressive complex 1.1 (PRC1.1) and a... more BCOR and its paralog BCORL1 encode subunits of the Polycomb repressive complex 1.1 (PRC1.1) and are recurrently mutated in myeloid malignancies. We show that leukemia-associated BCOR/BCORL1 mutations unlink the PRC1.1 RING-PCGF enzymatic core from the KDM2B-containing chromatin targeting auxiliary subcomplex, either by causing complete protein loss or expression of a C-terminally truncated protein lacking the PCGF Ub-like fold discriminator (PUFD) domain. By uncoupling PRC1.1 repressive function from target genes, BCOR/BCORL1 mutations activate aberrant cell signaling programs that confer acquired resistance to treatment. This study provides a mechanistic basis for Polycomb repressive dysfunction as a key oncogenic driver in myeloid malignancies and identifies a potential strategy for targeted therapy in BCOR-mutated cancer.

Research paper thumbnail of HEMATOPOIESIS AND STEM CELLS EPCR expression marks UM 171-expanded CD 34 1 cord blood stem cells

Human hematopoietic stem cells (HSCs) are defined by their ability to differentiate into all bloo... more Human hematopoietic stem cells (HSCs) are defined by their ability to differentiate into all blood lineages and to self-renew to sustain hematopoiesis throughout adult life. The low HSC frequency in biological specimens as well as our inability to purify HSCs to homogeneity have challenged the molecular characterization of these cells. HSC frequencies of 1 in 10 to 20 can be achieved by depleting CD38and CD45RA-expressing cells from uncultured human cord blood (CB) units and enriching for CD34-, CD90-, and CD49f-expressing cells, however, relying on these markers to evaluate HSC activity in vitro is not feasible because the expression of these markers changes dramatically when cells are introduced in culture (supplemental Figure 1, available on the Blood Web site). Dorell et al demonstrated that CD38 expression is lost in cultures initiated withCD34CD38 cells, which were reported to lack severe combined immunodeficiency– repopulating cell activity. CD90 cells were also shown to acqu...

Research paper thumbnail of MYCT1 Controls Environmental Sensing to Maintain Self-Renewal in Human Hematopoietic Stem Cells

Research paper thumbnail of S248: The Endosomal Adaptor Protein MYCT1 Controls Environmental Sensing in Human HSCS

Research paper thumbnail of Supplementary Figure from <i>BCOR</i> and <i>BCORL1</i> Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Research paper thumbnail of Supplementary Data from <i>BCOR</i> and <i>BCORL1</i> Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Supplementary Data from BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Si... more Supplementary Data from BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Research paper thumbnail of 2009 – the Endosomal Adaptor Protein MYCT1 Controls Human Hematopoietic Stem Cell Function

Experimental Hematology, Aug 1, 2021

Research paper thumbnail of Data from <i>BCOR</i> and <i>BCORL1</i> Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb ... more Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well-defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1-mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1 tumor-suppressive activity and identifies a therapeutic strategy in PRC1.1-mutated cancer.Significance:We demonstrate that BCOR and BCORL1 mutations in leukemia unlink PRC1.1 repressive function from target genes, resulting in epigenetic reprogramming and activation of aberrant cell signaling programs that mediate treatment resistance. Our study provides mechanistic insights into the pathogenesis of PRC1.1-mutated leukemia that inform novel therapeutic approaches.This article is highlighted in the In This Issue feature, p. 85

Research paper thumbnail of 3016 – MYCT1 Controls Human Hematopoietic Stem Cell Function by Moderating Endocytosis and Environmental Sensing

Research paper thumbnail of Supplementary Data from BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Supplementary Data from BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Si... more Supplementary Data from BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Research paper thumbnail of Data from BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes

Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb ... more Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well-defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1-mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1...

Research paper thumbnail of 2001 – the Endosomal Adaptor Protein MYCT1 Controls Environmental Sensing in Human Hematopoietic Stem Cells

Research paper thumbnail of 2023 – Two Distinct Isoforms of MLLT3 Balance Human HSC Fate Decisions

Research paper thumbnail of 2009 – the Endosomal Adaptor Protein MYCT1 Controls Human Hematopoietic Stem Cell Function

Research paper thumbnail of 2001 – the Endosomal Adaptor Protein MYCT1 Controls Environmental Sensing in Human Hematopoietic Stem Cells

Experimental Hematology, 2022

Research paper thumbnail of 3163 – Modulation of Rna Polymerase II Activity Regulates Human HSC Self-Renewal

Research paper thumbnail of 3037 – Two Distinct Isoforms of MLLT3 Regulate Human HSC Function

Research paper thumbnail of Mapping human haematopoietic stem cells from haemogenic endothelium to birth

Nature

Human hematopoietic stem cell (HSC) ontogeny is poorly defined due to the inability to identify H... more Human hematopoietic stem cell (HSC) ontogeny is poorly defined due to the inability to identify HSCs as they emerge and mature in different hematopoietic sites. We created a single-cell transcriptome map of human hematopoietic tissues from 1 st trimester to birth and found that HSC signature RUNX1+HOXA9+MLLT3+MECOM+HLF+SPINK2+ distinguishes HSCs from progenitors throughout gestation. In addition to the AGM (aorta-gonad-mesonephros) region, nascent HSCs populated the placenta and yolk sac before colonizing the liver at 6 weeks. Comparison of HSCs from different maturation stages revealed the establishment of HSC transcription factor machinery upon HSC emergence, whereas their surface phenotype evolved throughout development. HSC transition to the liver marked a molecular shift evidenced by suppression of surface antigens, reflecting nascent HSC identity, and acquisition of HSC maturity markers PROM1/CD133 and HLA-DR. HSC origin was tracked to ALDH1A1+KCNK17+ hemogenic endothelial (HE) cells, which arose from IL33+ALDH1A1+ arterial endothelial subset, termed pre-HE. Spatial transcriptomics and immunofluorescence visualized this process in ventrally located intra-aortic hematopoietic clusters. The in vivo map of human HSC ontogeny validated the generation of AGM-like definitive HSPCs from human pluripotent stem cells, and serves as a guide to improve their maturation to functional HSCs.

Research paper thumbnail of Decoding Human Hematopoietic Stem Cell Self-Renewal

Current Stem Cell Reports

Purpose of Review Hematopoietic stem cells (HSCs) maintain blood and immune cell homeostasis by b... more Purpose of Review Hematopoietic stem cells (HSCs) maintain blood and immune cell homeostasis by balancing quiescence, self-renewal, and differentiation. HSCs can be used in lifesaving transplantation treatments to create a healthy hematopoietic system in patients suffering from malignant or inherited blood diseases. However, lack of matching bone marrow donors, and the low quantity of HSCs in a single cord blood graft, are limitations for successful transplantation. The enormous regenerative potential of HSCs has raised the hope that HSC self-renewal could be recapitulated in culture to achieve robust expansion of HSCs for therapeutic use. Yet, when HSCs are cultured ex vivo their function becomes compromised, limiting successful expansion. Recent Findings After decades of efforts to expand human HSCs ex vivo that resulted in minimal increase in transplantable units, recent studies have helped define culture conditions that can increase functional HSCs. These studies have provided n...

Research paper thumbnail of BCOR and BCORL1 mutations drive epigenetic reprogramming and oncogenic signaling by unlinking PRC1.1 from target genes

Research paper thumbnail of BCOR and BCORL1 mutations disrupt PRC1.1 repressive function in leukemia by unlinking the RING-PCGF1 enzymatic core from target genes

bioRxiv, 2021

BCOR and its paralog BCORL1 encode subunits of the Polycomb repressive complex 1.1 (PRC1.1) and a... more BCOR and its paralog BCORL1 encode subunits of the Polycomb repressive complex 1.1 (PRC1.1) and are recurrently mutated in myeloid malignancies. We show that leukemia-associated BCOR/BCORL1 mutations unlink the PRC1.1 RING-PCGF enzymatic core from the KDM2B-containing chromatin targeting auxiliary subcomplex, either by causing complete protein loss or expression of a C-terminally truncated protein lacking the PCGF Ub-like fold discriminator (PUFD) domain. By uncoupling PRC1.1 repressive function from target genes, BCOR/BCORL1 mutations activate aberrant cell signaling programs that confer acquired resistance to treatment. This study provides a mechanistic basis for Polycomb repressive dysfunction as a key oncogenic driver in myeloid malignancies and identifies a potential strategy for targeted therapy in BCOR-mutated cancer.

Research paper thumbnail of HEMATOPOIESIS AND STEM CELLS EPCR expression marks UM 171-expanded CD 34 1 cord blood stem cells

Human hematopoietic stem cells (HSCs) are defined by their ability to differentiate into all bloo... more Human hematopoietic stem cells (HSCs) are defined by their ability to differentiate into all blood lineages and to self-renew to sustain hematopoiesis throughout adult life. The low HSC frequency in biological specimens as well as our inability to purify HSCs to homogeneity have challenged the molecular characterization of these cells. HSC frequencies of 1 in 10 to 20 can be achieved by depleting CD38and CD45RA-expressing cells from uncultured human cord blood (CB) units and enriching for CD34-, CD90-, and CD49f-expressing cells, however, relying on these markers to evaluate HSC activity in vitro is not feasible because the expression of these markers changes dramatically when cells are introduced in culture (supplemental Figure 1, available on the Blood Web site). Dorell et al demonstrated that CD38 expression is lost in cultures initiated withCD34CD38 cells, which were reported to lack severe combined immunodeficiency– repopulating cell activity. CD90 cells were also shown to acqu...