Somatic genetic rescue in hematopoietic cells in GATA2 deficiency

Catto, Luiz Fernando Bazzo; Borges, Gustavo; Pinto, André Luíz de Carvalho Braule; Clé, Diego V.; Chahud, Fernando; Santana, Bárbara Amélia Aparecida; Donaires, Flávia S.; Calado, Rodrigo T.

doi:10.1182/blood.2020005538

Cited by 31 publications

(30 citation statements)

References 15 publications

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“…We propose that the selective advantage provided by the somatic EIF6-R61L mutation promoted the expansion of the SBDS-deficient HSPCs to repopulate the hematopoietic system to a VAF close to 50% in peripheral blood DNA. Similar phenomena have been observed in other Mendelian hematopoietic disorders 14 – 16 .…”

Section: Discussionsupporting

confidence: 87%

“…However, more than 40 years ago, Weill and Reynaud proposed that in certain circumstances, somatic mutations might be beneficial to the cell without inducing disease or cellular transformation 12 . In inherited Mendelian diseases, this phenomenon, dubbed somatic genetic rescue (SGR) 13 , is considered rare and has mainly been observed in hematopoietic disorders, where it may confer a selective advantage and promote recovery of hematopoiesis by counteracting the deleterious effect of the germline mutation 14 – 16 . In most cases, SGR affects the germline mutated gene (direct SGR 13 ).…”

Section: Introductionmentioning

confidence: 99%

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Somatic genetic rescue of a germline ribosome assembly defect

et al. 2021

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Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Somatic genetic rescue of a germline ribosome assembly defect

et al. 2021

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“…In this scenario, selective 2A, B). In the context of the basic pathology with bone marrow failure or neutropenia-that is, the function of an affected gene being equally essential for some or all hematopoietic lineages-reversion mutations have been detected in cells other than lymphoid lineages, as observed in SAMD9/SAMD9L syndrome, MYSM1 deficiency, WHIM syndrome, GATA2 deficiency, and Fanconi anemia (94,96,98,105,106,112) (Table 3 and Figure 2C). For the aforementioned reasons, reversion mutations may be predominant in Tcell populations.…”

Section: Discussionmentioning

confidence: 99%

Reversion Mosaicism in Primary Immunodeficiency Diseases

Miyazawa

Wada

2021

Front. Immunol.

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Reversion mosaicism has been reported in an increasing number of genetic disorders including primary immunodeficiency diseases. Several mechanisms can mediate somatic reversion of inherited mutations. Back mutations restore wild-type sequences, whereas second-site mutations result in compensatory changes. In addition, intragenic recombination, chromosomal deletions, and copy-neutral loss of heterozygosity have been demonstrated in mosaic individuals. Revertant cells that have regained wild-type function may be associated with milder disease phenotypes in some immunodeficient patients with reversion mosaicism. Revertant cells can also be responsible for immune dysregulation. Studies identifying a large variety of genetic changes in the same individual further support a frequent occurrence of reversion mosaicism in primary immunodeficiency diseases. This phenomenon also provides unique opportunities to evaluate the biological effects of restored gene expression in different cell lineages. In this paper, we review the recent findings of reversion mosaicism in primary immunodeficiency diseases and discuss its clinical implications.

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“…Interestingly, an asymptomatic germline GATA2 mutant individual acquired a somatic mutation reversing the harmful GATA2 mutation. This resulted in a selective advantage of the corrected HSCs and prevented from developing malignancy (Catto et al, 2020 ). Together this implicates having a few mutation-corrected HSCs might already have clinical significance for GATA2 haploinsufficiency patients.…”

Section: Genome Editing: a Cure For Gata2 Haploinsufficiencies?mentioning

confidence: 99%

From Basic Biology to Patient Mutational Spectra of GATA2 Haploinsufficiencies: What Are the Mechanisms, Hurdles, and Prospects of Genome Editing for Treatment

Koyunlar

Pater

2020

Front. Genome Ed.

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Inherited bone marrow failure syndromes (IBMFS) are monogenetic disorders that result in a reduction of mature blood cell formation and predisposition to leukemia. In children with myeloid leukemia the gene most often mutated is Gata binding protein 2 (GATA2) and 80% of patients with GATA2 mutations develop myeloid malignancy before the age of forty. Although GATA2 is established as one of the key regulators of embryonic and adult hematopoiesis, the mechanisms behind the leukemia predisposition in GATA2 haploinsufficiencies is ambiguous. The only curative treatment option currently available is allogeneic hematopoietic stem cell transplantation (allo-SCT). However, allo-SCT can only be applied at a relatively late stage of the disease as its applicability is compromised by treatment related morbidity and mortality (TRM). Alternatively, autologous hematopoietic stem cell transplantation (auto-SCT), which is associated with significantly less TRM, might become a treatment option if repaired hematopoietic stem cells would be available. Here we discuss the recent literature on leukemia predisposition syndromes caused by GATA2 mutations, current knowledge on the function of GATA2 in the hematopoietic system and advantages and pitfalls of potential treatment options provided by genome editing.

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Somatic genetic rescue in hematopoietic cells in GATA2 deficiency

Cited by 31 publications

References 15 publications

Somatic genetic rescue of a germline ribosome assembly defect

Somatic genetic rescue of a germline ribosome assembly defect

Reversion Mosaicism in Primary Immunodeficiency Diseases

From Basic Biology to Patient Mutational Spectra of GATA2 Haploinsufficiencies: What Are the Mechanisms, Hurdles, and Prospects of Genome Editing for Treatment

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