GATA2 deficiency and haematopoietic stem cell transplantation: challenges for the clinical practitioner

Bogaert, Debby; Laureys, Geneviève; Naesens, Leslie; Mazure, Dominiek; Bruyne, Marieke De; Hsu, Amy P.; Bordon, Victoria; Wouters, E.; Tavernier, Simon; Lambrecht, Bart N.; Baere, Elfride De; Haerynck, Filomeen; Kerre, Tessa

doi:10.1111/bjh.16247

Cited by 27 publications

(19 citation statements)

References 15 publications

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“…HSCT was shown to reverse HPV-related lesions as well respiratory problems (PAP) [ 68 , [103] , [104] , [105] ]. Patients with stable disease course, without relevant infections, bone marrow dysplasia and transfusion-dependency might qualify for a watch & wait strategy [ 106 , 107 ]. However, it can be assumed that most GATA2-deficient patients show progressive disease and even with careful watching the best opportunity for low risk HSCT might be missed.…”

Section: Gata2 Deficiencymentioning

confidence: 99%

Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

Sahoo

Kozyra

Wlodarski

2020

Best Practice & Research Clinical Haematology

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Increasing awareness about germline predisposition and the widespread application of unbiased whole exome sequencing contributed to the discovery of new clinical entities with high risk for the development of haematopoietic malignancies. The revised 2016 WHO classification introduced a novel category of “myeloid neoplasms with germline predisposition” with GATA2 , CEBPA , DDX41 , RUNX1 , ANKRD26 , and ETV6 genes expanding the spectrum of hereditary myeloid neoplasms (MN). Since then, more germline causes of MN were identified, including SAMD9 , SAMD9L , and ERCC6L2 . This review describes the genetic and clinical spectrum of predisposition to MN. The main focus lies in delineation of phenotypes, genetics and management of GATA2 deficiency and the novel SAMD9/SAMD9L-related disorders. Combined, GATA2 and SAMD9/SAMD9L (SAMD9/9L) syndromes are recognized as most frequent causes of primary pediatric myelodysplastic syndromes, particularly in setting of monosomy 7. To date, ∼550 cases with germline GATA2 mutations, and ∼130 patients with SAMD9/9L mutations had been reported in literature. GATA2 deficiency is a highly penetrant disorder with a progressive course that often rapidly necessitates bone marrow transplantation. In contrast, SAMD9/SAMD9L disorders show incomplete penetrance with various clinical outcomes ranging from spontaneous haematological remission observed in young children to malignant progression.

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Section: Gata2 Deficiencymentioning

confidence: 99%

Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

Sahoo

Kozyra

Wlodarski

2020

Best Practice & Research Clinical Haematology

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“…In germline GATA2 syndromes, patients with complications of immunodeficiency and/or low-grade MDS, demonstrated improved survival when transplanted at a younger age, with infection and graft-versus-host disease being the major causes of transplant-related mortality. [94][95][96] It has been suggested that the ideal time to proceed to alloSCT in GATA2 disorders is during the hypocellular state, prior to the onset of immunodeficiency, MDS or acquisition of karyotypic abnormalities. 97 Consideration of prophylactic alloSCT in germline CEBPA carriers has been discussed due to the high lifetime risk of AML (>80%) with these lesions.…”

Section: Indications For Allosctmentioning

confidence: 99%

Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges

2021

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Over the last decade, the field of hereditary haematological malignancy syndromes (HHMSs) has gained increasing recognition among clinicians and scientists worldwide. Germline mutations now account for almost 10% of adult and paediatric myelodysplasia/acute myeloid leukaemia (MDS/AML). As our ability to diagnose HHMSs has improved, we are now faced with the challenges of integrating these advances into routine clinical practice for patients with MDS/AML and how to optimise management and surveillance of patients and asymptomatic carriers. Discoveries of novel syndromes combined with clinical, genetic and epigenetic profiling of tumour samples, have highlighted unique patterns of disease evolution across HHMSs. Despite these advances, causative lesions are detected in less than half of familial cases and evidence-based guidelines are often lacking, suggesting there is much still to learn. Future research efforts are needed to sustain current momentum within the field, led not only by advancing genetic technology but essential collaboration between clinical and academic communities.

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“…Otherwise, patients with GATA2 deficiency present variable grade of immunodeficiency and other comorbidity that could threaten the outcome of HSCT with a high rate of transplant related toxicity. Interestingly, different case series reported thrombotic complications after HSCT in GATA2 deficient patients, sometimes with a fatal outcome [ 36 , 38 , 39 ].…”

Section: Managementmentioning

confidence: 99%

GATA2 Related Conditions and Predisposition to Pediatric Myelodysplastic Syndromes

Bruzzese

Leardini

Masetti

et al. 2020

Cancers

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Myelodysplastic syndromes (MDS) are hematopoietic disorders rare in childhood, often occurring in patients with inherited bone marrow failure syndromes or germinal predisposition syndromes. Among the latter, one of the most frequent involves the gene GATA binding protein 2 (GATA2), coding for a transcriptional regulator of hematopoiesis. The genetic lesion as well as the clinical phenotype are extremely variable; many patients present hematological malignancies, especially MDS with the possibility to evolve into acute myeloid leukemia. Variable immune dysfunction, especially resulting in B- and NK-cell lymphopenia, lead to severe infections, including generalized warts and mycobacterial infection. Defects of alveolar macrophages lead to pulmonary alveolar proteinosis through inadequate clearance of surfactant proteins. Currently, there are no clear guidelines for the monitoring and treatment of patients with GATA2 mutations. In patients with MDS, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT) that restores normal hematopoiesis preventing the progression to acute myeloid leukemia and clears long-standing infections. However, to date, the donor type, conditioning regimen, and the optimal time to proceed to HSCT, as well as the level of chimerism needed to reverse the phenotype, remain unclear highlighting the need for consensus guidelines.

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GATA2 deficiency and haematopoietic stem cell transplantation: challenges for the clinical practitioner

Cited by 27 publications

References 15 publications

Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges

GATA2 Related Conditions and Predisposition to Pediatric Myelodysplastic Syndromes

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