Non-genetic mechanisms of therapeutic resistance in cancer

Nature reviews. Cancer, Journal Year: 2020, Volume and Issue: 20(12), P. 743 - 756

Published: Oct. 8, 2020

Language: Английский

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Myelodysplastic Syndromes

New England Journal of Medicine, Journal Year: 2020, Volume and Issue: 383(14), P. 1358 - 1374

Published: Sept. 30, 2020

MDS are clonal hematopoietic disorders involving morphologic defects and peripheral-blood cytopenias, with a risk of progression to acute myeloid leukemia. Except for del(5q) MDS, which is responsive lenalidomide, these largely managed supportive care.

Language: Английский

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Understanding intrinsic hematopoietic stem cell aging

Haematologica, Journal Year: 2019, Volume and Issue: 105(1), P. 22 - 37

Published: Dec. 5, 2019

Hematopoietic stem cells (HSC) sustain blood production over the entire life-span of an organism. It is extreme importance that these maintain self-renewal and differentiation potential time in order to preserve homeostasis hematopoietic system. Many intrinsic aspects HSC are affected by aging process resulting a deterioration their potential, independently microenvironment. Here we review recent findings characterizing most aged HSC, ranging from phenotypic molecular alterations. Historically, DNA damage was thought be main cause aging. However, years, many new have defined increasing number biological processes intrinsically change with age HSC. Epigenetics chromatin architecture, together autophagy, proteostasis metabolic changes, how they interconnected, acquiring growing for understanding cells. Given increase populations older subjects worldwide, considering primary risk factor diseases, becomes particularly relevant also context hematologic disorders, such as myelodysplastic syndromes acute myeloid leukemia. Research on mechanisms responsible providing, will continue provide, targets possibly ameliorate or delay system consequently improve outcome disorders elderly. The niche-dependent contributions discussed another this same issue Journal.

Language: Английский

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Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS

The Journal of Experimental Medicine, Journal Year: 2021, Volume and Issue: 218(7)

Published: June 15, 2021

With a growing aged population, there is an imminent need to develop new therapeutic strategies ameliorate disorders of hematopoietic aging, including clonal hematopoiesis and myelodysplastic syndrome (MDS). Cell-intrinsic dysregulation innate immune- inflammatory-related pathways as well systemic inflammation have been implicated in defects associated with hematopoiesis, MDS. Here, we review discuss the role dysregulated immune inflammatory signaling that contribute competitive advantage dominance preleukemic MDS-derived cells. We also propose how emerging concepts will further reveal critical biology novel opportunities.

Language: Английский

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Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome

Nature Cell Biology, Journal Year: 2022, Volume and Issue: 24(3), P. 299 - 306

Published: March 1, 2022

Abstract Transfer RNA-derived fragments (tRFs) are emerging small noncoding RNAs that, although commonly altered in cancer, have poorly defined roles tumorigenesis 1 . Here we show that pseudouridylation (Ψ) of a stem cell-enriched tRF subtype 2 , mini tRFs containing 5′ terminal oligoguanine (mTOG), selectively inhibits aberrant protein synthesis programmes, thereby promoting engraftment and differentiation haematopoietic progenitor cells (HSPCs) patients with myelodysplastic syndrome (MDS). Building on evidence mTOG-Ψ targets polyadenylate-binding cytoplasmic (PABPC1), employed isotope exchange proteomics to reveal critical interactions between mTOG functional RNA-recognition motif (RRM) domains PABPC1. Mechanistically, this hinders the recruitment translational co-activator PABPC1-interacting (PAIP1) 3 strongly represses translation transcripts sharing pyrimidine-enriched sequences (PES) at untranslated region (UTR), including oligopyrimidine tracts (TOP) encode machinery components frequently cancer 4 Significantly, dysregulation leads aberrantly increased PES messenger RNA (mRNA) malignant MDS-HSPCs is clinically associated leukaemic transformation reduced patient survival. These findings define role for Ψ difficult-to-treat subsets MDS characterized by high risk progression acute myeloid leukaemia (AML).

Language: Английский

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Clonal haematopoiesis and dysregulation of the immune system

Nature reviews. Immunology, Journal Year: 2023, Volume and Issue: 23(9), P. 595 - 610

Published: March 20, 2023

Language: Английский

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TMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 2, 2024

Abstract Acute myeloid leukemia (AML) is initiated and sustained by a hierarchy of stem cells (LSCs), elimination this cell population required for curative therapies. Here we show that transmembrane immunoglobulin domain containing 2 (TMIGD2), recently discovered co-stimulatory immune receptor, aberrantly expressed human AML cells, can be used to identify enrich functional LSCs. We demonstrate TMIGD2 the development maintenance self-renewal LSCs but not essential normal hematopoiesis. Mechanistically, promotes proliferation, blocks differentiation increases cell-cycle via an ERK1/2-p90RSK-CREB signaling axis. Targeting with anti-TMIGD2 monoclonal antibodies attenuates LSC reduces burden in patient-derived xenograft models has negligible effect on hematopoietic stem/progenitor cells. Thus, our studies reveal function provide promising therapeutic strategy AML.

Language: Английский

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Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial

Nature Medicine, Journal Year: 2020, Volume and Issue: 26(12), P. 1852 - 1858

Published: Oct. 26, 2020

Language: Английский

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Dysregulated haematopoietic stem cell behaviour in myeloid leukaemogenesis

Nature reviews. Cancer, Journal Year: 2020, Volume and Issue: 20(7), P. 365 - 382

Published: May 15, 2020

Language: Английский

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CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

Cancers, Journal Year: 2019, Volume and Issue: 11(9), P. 1358 - 1358

Published: Sept. 12, 2019

The interleukin-3 receptor alpha chain (IL-3R), more commonly referred to as CD123, is widely overexpressed in various hematological malignancies, including acute myeloid leukemia (AML), B-cell lymphoblastic leukemia, hairy cell Hodgkin lymphoma and particularly, blastic plasmacytoid dendritic neoplasm (BPDCN). Importantly, CD123 expressed at both the level of leukemic stem cells (LSCs) differentiated blasts, which makes an attractive therapeutic target. Various agents have been developed drugs able target on malignant normal counterpart. Tagraxofusp (SL401, Stemline Therapeutics), a recombinant protein composed truncated diphtheria toxin payload fused IL-3, was approved for use patients with BPDCN December 2018 showed some clinical activity AML. Different monoclonal antibodies directed against are under evaluation antileukemic drugs, showing promising results either treatment AML minimal residual disease or relapsing/refractory BPDCN. Finally, recent studies exploring T expressing chimeric antigen receptor-modified T-cells (CAR T) new immunotherapy refractory/relapsing In 2018, MB-102 CAR by Mustang Bio Inc. received Orphan Drug Designation conclusion, these strongly support important BPDCN, while possible other malignancies will be evaluated ongoing studies.

Language: Английский

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