Germline GATA1 exon 2 mutation associated with chronic cytopenia and a non-down syndrome transient abnormal myelopoiesis with clonal trisomy 21

Camargo, Ricardo; Sahoo, Sushree Sangita; Córdoba, José Carlos; Magalhães, Isis Quezado

doi:10.1038/s41375-022-01638-6

Cited by 8 publications

(5 citation statements)

References 15 publications

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“…For example, point mutations in trisomy 21 iPSCs show GATA1s impairs megakaryocytic differentiation, by inducing the emergency of megakaryoblasts with major platelet and a-granule formation impairments ( 178 ). Conversely, acquired trisomy 21 has been reported in a patient carrying a germline GATA1 variant causing increased GATA1s, and associating with chronic anemia and thrombocytopenia as well as transient abnormal myelopoiesis, although the latter is likely a result of the trisomy 21 ( 179 ).…”

Section: Biological Mechanisms Of Bmf And/or Hm Predisposition Tfsmentioning

confidence: 99%

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

Zerella,

Homan,

Arts

et al. 2023

Front. Oncol.

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Transcription factors (TFs) play a critical role as key mediators of a multitude of developmental pathways, with highly regulated and tightly organized networks crucial for determining both the timing and pattern of tissue development. TFs can act as master regulators of both primitive and definitive hematopoiesis, tightly controlling the behavior of hematopoietic stem and progenitor cells (HSPCs). These networks control the functional regulation of HSPCs including self-renewal, proliferation, and differentiation dynamics, which are essential to normal hematopoiesis. Defining the key players and dynamics of these hematopoietic transcriptional networks is essential to understanding both normal hematopoiesis and how genetic aberrations in TFs and their networks can predispose to hematopoietic disease including bone marrow failure (BMF) and hematological malignancy (HM). Despite their multifaceted and complex involvement in hematological development, advances in genetic screening along with elegant multi-omics and model system studies are shedding light on how hematopoietic TFs interact and network to achieve normal cell fates and their role in disease etiology. This review focuses on TFs which predispose to BMF and HM, identifies potential novel candidate predisposing TF genes, and examines putative biological mechanisms leading to these phenotypes. A better understanding of the genetics and molecular biology of hematopoietic TFs, as well as identifying novel genes and genetic variants predisposing to BMF and HM, will accelerate the development of preventative strategies, improve clinical management and counseling, and help define targeted treatments for these diseases.

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Section: Biological Mechanisms Of Bmf And/or Hm Predisposition Tfsmentioning

confidence: 99%

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

Zerella,

Homan,

Arts

et al. 2023

Front. Oncol.

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“…Recently, long-term hematopoietic stem cells in the DS fetal liver were shown to be the cellular target of GATA1 mutations and the cell of origin in TAM . In rare instances, the same events may cooperate in the reverse sequence, ie, a germline GATA1 mutation followed by acquired trisomy 21 resulting in TAM . In most newborns, TAM resolves spontaneously, through mechanisms that are yet to be defined, and does not require intervention .…”

Section: Transient Abnormal Myelopoiesis (Tam)mentioning

confidence: 99%

“…10 In rare instances, the same events may cooperate in the reverse sequence, ie, a germline GATA1 mutation followed by acquired trisomy 21 resulting in TAM. 24 In most newborns, TAM resolves spontaneously, through mechanisms that are yet to be defined, and does not require intervention. 4,25 Approximately 20% to 30% of infants with TAM subsequently go on to develop ML-DS within the first 4 years of life at a median age of 18 months (Figure 1).…”

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confidence: 99%

Management of Down Syndrome–Associated Leukemias

et al. 2023

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ImportanceDown syndrome (DS), caused by an extra copy of material from chromosome 21, is one of the most common genetic conditions. The increased risk of acute leukemia in DS (DS-AL) has been recognized for decades, consisting of an approximately 150-fold higher risk of acute myeloid leukemia (AML) before age 4 years, and a 10- to 20-fold higher risk of acute lymphoblastic leukemia (ALL), compared with children without DS.ObservationsA recent National Institutes of Health-sponsored conference, ImpacT21, reviewed research and clinical trials in children, adolescents, and young adults (AYAs) with DS-AL and are presented herein, including presentation and treatment, clinical trial design, and ethical considerations for this unique population. Between 10% to 30% of infants with DS are diagnosed with transient abnormal myelopoiesis (TAM), which spontaneously regresses. After a latency period of up to 4 years, 20% to 30% develop myeloid leukemia associated with DS (ML-DS). Recent studies have characterized somatic mutations associated with progression from TAM to ML-DS, but predicting which patients will progress to ML-DS remains elusive. Clinical trials for DS-AL have aimed to reduce treatment-related mortality (TRM) and improve survival. Children with ML-DS have better outcomes compared with non-DS AML, but outcomes remain dismal in relapse. In contrast, patients with DS-ALL have inferior outcomes compared with those without DS, due to both higher TRM and relapse. Management of relapsed leukemia poses unique challenges owing to disease biology and increased vulnerability to toxic effects. Late effects in survivors of DS-AL are an important area in need of further study because they may demonstrate unique patterns in the setting of chronic medical conditions associated with DS.Conclusions and RelevanceOptimal management of DS-AL requires specific molecular testing, meticulous supportive care, and tailored therapy to reduce TRM while optimizing survival. There is no standard approach to treatment of relapsed disease. Future work should include identification of biomarkers predictive of toxic effects; enhanced clinical and scientific collaborations; promotion of access to novel agents through innovative clinical trial design; and dedicated studies of late effects of treatment.

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“…In individuals without T21, germline GATA1s mutations lead to congenital cytopenias but are not associated with a leukemic predisposition, 18,19 while co-occurring GATA1s mutations and acquired T21 in leukemic clones give rise to a ML-DS-like phenotype. [20][21][22] Previous studies have shown that the extra copy of chromosome 21 (HSA21) itself perturbs histone modifications throughout the genome and that the addition of a GATA1s mutation further perturbs acetylation specifically at genes involved in hematopoiesis and cell-cycle regulation, 23,24 suggesting that genomewide gene dysregulation underlies the hematopoietic and other end-organ manifestations of DS. These findings emphasize the unique genetic interactions between T21 and GATA1.…”

Section: Introductionmentioning

confidence: 99%

Single-cell transcriptomics reveal synergistic and antagonistic effects of T21 and GATA1s on hematopoiesis

Takasaki,

Wafula,

Kumar

et al. 2024

Preprint

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Trisomy 21 (T21), or Down syndrome (DS), is associated with baseline macrocytic erythrocytosis, thrombocytopenia, and neutrophilia, and transient abnormal myelopoiesis (TAM) and myeloid leukemia of DS (ML-DS). TAM and ML-DS blasts both arise from an aberrant megakaryocyte-erythroid progenitor and exclusively express GATA1s, the truncated isoform of GATA1, while germline GATA1s mutations in a non-T21 context lead to congenital cytopenias without a leukemic predisposition. This suggests that T21 and GATA1s perturb hematopoiesis independently and synergistically, but this interaction has been challenging to study in part due to limited human cell and murine models. To dissect the developmental impacts of GATA1s on hematopoiesis in euploid and T21 cells, we performed a single-cell RNA-sequencing timecourse on hematopoietic progenitors (HPCs) derived from isogenic human induced pluripotent stem cells differing only by chromosome 21 and/or GATA1 status. These HPCs were surprisingly heterogeneous and displayed spontaneous lineage skew apparently dictated by T21 and/or GATA1s. In euploid cells, GATA1s nearly eliminated erythropoiesis, impaired MK maturation, and promoted an immature myelopoiesis, while in T21 cells, GATA1s appeared to compete with the enhanced erythropoiesis and suppressed megakaryopoiesis driven by T21 to give rise to immature erythrocytes, MKs, and myeloid cells. T21 and GATA1s both disrupted temporal regulation of lineage-specific transcriptional programs and specifically perturbed cell cycle genes. These findings in an isogenic system can thus be attributed specifically to T21 and GATA1s and suggest that these genetic changes together enhance HPC proliferation at the expense of maturation, consistent with a pro-leukemic phenotype.

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Germline GATA1 exon 2 mutation associated with chronic cytopenia and a non-down syndrome transient abnormal myelopoiesis with clonal trisomy 21

Cited by 8 publications

References 15 publications

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

Management of Down Syndrome–Associated Leukemias

Single-cell transcriptomics reveal synergistic and antagonistic effects of T21 and GATA1s on hematopoiesis

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