MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia

Rodríguez, Alfredo; Zhang, Kaiyang; Färkkilä, Anniina; Filiatrault, Jessica; Yang, Chunyu; Velázquez, Martha; Furutani, Elissa; Goldman, Devorah C.; Teresa, Benilde García de; Garza-Mayén, Gilda; McQueen, Kelsey; Sambel, Larissa A.; Molina, Bertha; Torres, Leda; González, Marisol I.; Vadillo, Eduardo; Pelayo, Rosana; Fleming, William H.; Grompe, Markus; Shimamura, Akiko; Hautaniemi, Sampsa; Greenberger, Joel S.; Frı́as, Sara; Parmar, Kalindi; D’Andrea, Alan D.

doi:10.1016/j.stem.2020.09.004

Cited by 41 publications

(34 citation statements)

References 73 publications

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“…This can be accounted by documented interferon-gamma overexpression in FA HSPCs 9,10 , and this cytokine's transactivation of classical and non-classical HLA class I genes, such as the HLA-A, HLA-C and HLA-E genes 11,12 . Although it might be expected that p53 or Myc -which have been shown to be upregulated in FA patients 7,13 -should be also downregulated in corrected FA HSPCs, our data do not support this hypothesis. Reasons accounting for these apparent unexpected observations could be related either to the enhanced expression of cell cycle genes in corrected FA HSPCs, or to post-transcriptional regulatory mechanisms involved in p53 expression 7 , and also to the moderate BMF status of the FA patients enrolled in the FANCOLEN I trial 1 .…”

Section: Discussioncontrasting

confidence: 91%

Gene Therapy Restores the Transcriptional Program of Hematopoietic Stem Cells in Fanconi Anemia

Lasaga

Rı́o

Vilas–Zornoza

et al. 2021

Preprint

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Fanconi anemia (FA) is a monogenic inherited disease associated with mutations in genes that encode for proteins participating in the FA/BRCA DNA repair pathway. Mutations in FA genes result in chromosomal instability and cell death, leading to cancer risks and progressive cell mortality, most notably in hematopoietic stem and progenitor cells (HSPC). Recently, we showed the first clinical evidence that gene therapy confers engraftment and proliferative advantage of gene-corrected HSPCs in FA patients1. Despite this and many other gene therapy advances, the question of whether the molecular pathways affected in monogenic diseases can be reverted by lentiviral-mediated gene therapy has never been addressed. This is even more challenging in DNA repair syndromes such as FA since in these cases, transcriptional defects in affected cells might not be restored due to DNA damage accumulated prior to gene therapy. Using single-cell RNA sequencing in HSPCs from FA-A patients previously treated by ex vivo gene therapy, we demonstrate that lentiviral-mediated gene therapy prior to severe bone marrow failure not only restores the expression of the defective gene, but also induces a long-term correction of the transcriptional program in FA HSPCs, which then acquire a signature characteristic of healthy HSPCs. Our results reveal new molecular evidence showing the potential of gene therapy to fully rescue phenotypic defects in FA, a devastating HSPC disease characterized by defective DNA repair.

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Section: Discussioncontrasting

confidence: 91%

Gene Therapy Restores the Transcriptional Program of Hematopoietic Stem Cells in Fanconi Anemia

Lasaga

Rı́o

Vilas–Zornoza

et al. 2021

Preprint

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“…Additionally, 127 of the 1053 DEGs identified by our bulk RNAseq analysis are direct MYC targets, 78 of which were differential expressed in BM-Treg consistent with inhibition of MYC signaling. MYC drives cell cycle and proliferation in response to TCR and IL-2 (Tzachanis et al, 2004;Chapman et al, 2020;Rodriguez et al, 2021) which are also predicted to be downregulated in BM-Treg (Figure 4D) suggesting this subset is in a more quiescent and less proliferative state than pTreg. Supporting this, fewer BM-Treg expressed Ki-67, and cell cycle analysis showed an increased proportion of BM-Treg over SP-Treg in G0, and thus quiescent ( Figures 4E,F).…”

Section: Bm-treg Exhibit a Distinct Transcriptional Profilementioning

confidence: 91%

Bone Marrow Regulatory T Cells Are a Unique Population, Supported by Niche-Specific Cytokines and Plasmacytoid Dendritic Cells, and Required for Chronic Graft-Versus-Host Disease Control

Nicholls

Cao

Texier

et al. 2021

Front. Cell Dev. Biol.

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Regulatory T cell (Treg) reconstitution is essential for reestablishing tolerance and maintaining homeostasis following stem-cell transplantation. We previously reported that bone marrow (BM) is highly enriched in autophagy-dependent Treg and autophagy disruption leads to a significant Treg loss, particularly BM-Treg. To correct the known Treg deficiency observed in chronic graft-versus-host disease (cGVHD) patients, low dose IL-2 infusion has been administered, substantially increasing peripheral Treg (pTreg) numbers. However, as clinical responses were only seen in ∼50% of patients, we postulated that pTreg augmentation was more robust than for BM-Treg. We show that BM-Treg and pTreg have distinct characteristics, indicated by differential transcriptome expression for chemokine receptors, transcription factors, cell cycle control of replication and genes linked to Treg function. Further, BM-Treg were more quiescent, expressed lower FoxP3, were highly enriched for co-inhibitory markers and more profoundly depleted than splenic Treg in cGVHD mice. In vivo our data are consistent with the BM and not splenic microenvironment is, at least in part, driving this BM-Treg signature, as adoptively transferred splenic Treg that entered the BM niche acquired a BM-Treg phenotype. Analyses identified upregulated expression of IL-9R, IL-33R, and IL-7R in BM-Treg. Administration of the T cell produced cytokine IL-2 was required by splenic Treg expansion but had no impact on BM-Treg, whereas the converse was true for IL-9 administration. Plasmacytoid dendritic cells (pDCs) within the BM also may contribute to BM-Treg maintenance. Using pDC-specific BDCA2-DTR mice in which diptheria toxin administration results in global pDC depletion, we demonstrate that pDC depletion hampers BM, but not splenic, Treg homeostasis. Together, these data provide evidence that BM-Treg and splenic Treg are phenotypically and functionally distinct and influenced by niche-specific mediators that selectively support their respective Treg populations. The unique properties of BM-Treg should be considered for new therapies to reconstitute Treg and reestablish tolerance following SCT.

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“…Recent data illuminate this through single cell RNA sequencing of primary HSPCs from FA patients that showed overexpression of the MYC oncogene occurs in a subset of FA HSPCs and appears to be a counteracting force against the growth suppressive activities of TGFβ and p53, since inhibition of MYC expression reduces the proliferative capacity of FA HSPCs. MYC overexpression in FA cells, however, is a double-edged sword that allows the progression of FA cells through the cell cycle but at the same time increases their replicative stress [ 106 ] and concomitant CIN, a FA characteristic that is tightly related to clonal evolution that precedes neoplasia.…”

Section: Clinical Consequences Of Fa/brca Pathway Failurementioning

confidence: 99%

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

García-de-Teresa

Rodríguez

Frı́as

2020

Genes

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Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, which cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is impaired and accumulation of toxic DNA double strand breaks occurs. To repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, which may lead to the formation of gross structural chromosome aberrations of which radial figures are the hallmark of FA, and their segregation during cell division are the origin of subsequent aberrations such as translocations, dicentrics and acentric fragments. The deficiency in DNA repair has pleiotropic consequences in the phenotype of patients with FA, including developmental alterations, bone marrow failure and an extreme risk to develop cancer. The mechanisms leading to the physical abnormalities during embryonic development have not been clearly elucidated, however FA has features of premature aging with chronic inflammation mediated by pro-inflammatory cytokines, which results in tissue attrition, selection of malignant clones and cancer onset. Moreover, chromosomal instability and cell death are not exclusive of the somatic compartment, they also affect germinal cells, as evidenced by the infertility observed in patients with FA.

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MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia

Cited by 41 publications

References 73 publications

Gene Therapy Restores the Transcriptional Program of Hematopoietic Stem Cells in Fanconi Anemia

Gene Therapy Restores the Transcriptional Program of Hematopoietic Stem Cells in Fanconi Anemia

Bone Marrow Regulatory T Cells Are a Unique Population, Supported by Niche-Specific Cytokines and Plasmacytoid Dendritic Cells, and Required for Chronic Graft-Versus-Host Disease Control

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

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