Myeloid Neoplasms with Germline GATA2 Mutation
Alexandria Avery, DO
Daynna J. Wolff, PhD
- Myeloid Neoplasms/Acute myeloid leukemia
- Myelodysplastic Syndrome
Cancer Sub-Classification / Subtype
- Acute Myeloid Leukemia (AML) with GATA2 germline mutation
Definition / Description of Disease
This is a distinct entity in the World Health Organization (WHO) classification system within the section of Myeloid Neoplasms with Germline Predisposition. Acute myeloid leukemia with GATA2 mutation is a rare inherited germline predisposition mutation. It is associated with multiple clinical features and rare genetic disorders including MonoMAC or DCML Syndrome, Emberger Syndrome, and familial myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). Other genes identified in the familial AML-MDS disease category include RUNX1 and CEBPA.
Synonyms / Terminology
- Familial acute myeloid leukemia-myelodysplastic syndrome
Epidemiology / Prevalence
- Germline GATA 2 mutations are a rare cause of familial MDS and AML, but the prevalence of the disorder is unknown.
- In a small series of MDS-AML cases, GATA2 mutations were identified in 4 of 12 (33 percent) and 4 of 27 (15 percent) families.
- MDS/AML develops in approximately 70 percent of affected individuals at a median age of onset of 29 years (range 0.4 to 78 years).
- Hematologic parameters may be normal prior to the development of MDS -AML or may present with monocytopenia, lymphopenia, or less frequently neutropenia.
- Defects in the GATA2 gene have led to a variety of clinical phenotypes that are inherited as autosomal dominant disorders with reduced penetrance:
- Familial MDS-AML: Individuals can present without any hematopoietic or organ system manifestations prior to the development of MDS or AML.
- Emberger Syndrome: Patients present with primary lymphedema, sensorineural deafness, cutaneous warts, and low CD4/CD8 T cell ratio, along with a predisposition for MDS-AML.
- MonoMAC or DCML Syndrome : Complex immunodeficiency characterized by monocytopenia, B-cell and NK-cell lymphocytopenia, near absent natural killer cells, and increased susceptibility to mycobacterium or papilloma virus infections, pulmonary alveolar proteinosis, along with a predisposition for MDS-AML.
Sites of Involvement
AML-MDS with GATA2 mutation affects the hematopoietic and lymphatic systems.
This entity is based on a genetic predisposition. Morphological features would be specific to the disease the patient develops.
This germline genetic defect leads to a predisposition to myeloid malignancies. The immunophenotype would be specific for the disease that the patient develops.
Chromosomal Rearrangements (Gene Fusions)
Characteristic Chromosomal Aberrations / Patterns
- Chromosomal aberrations would be specific for the disease that the patient develops. Common aberrations seen in MDS in these patients include typical anormalities: monosomy 7, trisomy 8, and trisomy 21.
These changes would be specific for the disease that the patient develops.
Gene Mutations (SNV/INDEL)
- Mutations described have marked heterogeneity, variability, and present throughout the GATA2 gene. The most common mutation identified is a missense mutation (Thr354Met); however, insertions, deletions, and single base substitutions have also been described. Two major classes of mutations have been identified. The first being an N-terminal frameshift mutation that results in a nonfunctional protein lacking most of the C-terminal. The second includes mutations in GATA2’s first and second zinc fingers.
- Mutations in ASXL1 are frequently acquired at the time of malignant progression. As in sporadic disease with ASXL1 mutation, these mutations have a poor prognosis in germline mutation carriers.
Genes and Main Pathways Involved
- Monoallelic mutations in GATA2, located on chromosome band 3q21.3
- The GATA2 gene codes for a transcription factor that is involved in hematopoietic differentiation and lymphatic formation.
- GATA2 is probably an important predisposing mutation but secondary genetic events are required for the development of overt malignant disease.
Diagnostic Testing Methods
- Diagnosis of a familial AL/MDS syndrome is based on detection of the causal genetic abnormality in germline tissue (i.e., non-hematologic cells).
- Recommended diagnostic testing includes GATA2 exon sequencing, intron 5 enhancer region sequencing, and gene rearrangement testing.
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
- There is no agreed-upon protocol for optimal management of individuals diagnosed with a familial AL/MDS syndrome. The schedule and nature of monitoring must be individualized.
- The high incidence of MDS/AML in these individuals warrants close monitoring for any signs or symptoms of these malignancies.
- Allogeneic HCT has been successfully performed for a number of individuals with this syndrome and is the subject of an ongoing clinical trial (NCT01861106).
- HLA-matched relatives should be screened for the familial mutation and those carrying the mutation should be avoided.
- MonoMAC Syndrome
- Emberger Syndrome
- Familial AML-MDS
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