Myeloid Neoplasms with Germline GATA2 Mutation

From Compendium of Cancer Genome Aberrations
Jump to navigation Jump to search

Primary Author(s)*

Alexandria Avery, DO

Daynna J. Wolff, PhD

Cancer Category/Type

  • 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[1]. 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[2][3].

Synonyms / Terminology

  • Familial acute myeloid leukemia-myelodysplastic syndrome[2]

Epidemiology / Prevalence

  • Germline GATA 2 mutations are a rare cause of familial MDS and AML, but the prevalence of the disorder is unknown[2][3][4].
  • 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[5].
  • 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)[6].

Clinical Features

  • Hematologic parameters may be normal prior to the development of MDS -AML  or may present with monocytopenia, lymphopenia, or less frequently neutropenia[7][8][9].
  • Defects in the GATA2 gene have led to a variety of clinical phenotypes that are inherited as autosomal dominant disorders with reduced penetrance[2][4]:
  1. Familial MDS-AML:  Individuals can present without any hematopoietic or organ system manifestations prior to the development of MDS or AML[2][3].
  2. 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[2][10].
  3. 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[2][11][12].

Sites of Involvement

AML-MDS with GATA2 mutation affects the hematopoietic and lymphatic systems[2].

Morphologic Features

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)

Not applicable

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[2][7][8][13][14].

Genomic Gain/Loss/LOH

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[2]. 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[2][4].

Other Mutations

  • 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[15][16].

Epigenomics (Methylation)

Genes and Main Pathways Involved

  • Monoallelic mutations in GATA2, located on chromosome band 3q21.3[7]
  • The GATA2 gene codes for a transcription factor that is involved in hematopoietic differentiation and lymphatic formation[2].
  • GATA2 is probably an important predisposing mutation but secondary genetic events are required for the development of overt malignant disease[2].

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)[3].
  • Recommended diagnostic testing includes GATA2 exon sequencing, intron 5 enhancer region sequencing, and gene rearrangement testing[3].

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[3].
  • The high incidence of MDS/AML in these individuals warrants close monitoring for any signs or symptoms of these malignancies[3].
  • Allogeneic HCT has been successfully performed for a number of individuals with this syndrome[8][17] 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[3].

Familial Forms

  • MonoMAC Syndrome
  • Emberger Syndrome
  • Familial AML-MDS

Other Information

Put your text here



Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Mutations


  1. Peterson LC, et al., (2017). Myeloid neoplasms with germline predisposition in WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p126-128.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 Gao, Juehua; et al. (2014). "Heritable GATA2 mutations associated with familial AML-MDS: a case report and review of literature". Journal of Hematology & Oncology. 7: 36. doi:10.1186/1756-8722-7-36. ISSN 1756-8722. PMC 4006458. PMID 24754962.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 UpToDate,
  4. 4.0 4.1 4.2 Hyde, R. Katherine; et al. (2011). "GATA2 mutations lead to MDS and AML". Nature Genetics. 43 (10): 926–927. doi:10.1038/ng.949. ISSN 1546-1718. PMID 21956389.
  5. Holme, Harriet; et al. (2012). "Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia". British Journal of Haematology. 158 (2): 242–248. doi:10.1111/j.1365-2141.2012.09136.x. ISSN 1365-2141. PMID 22533337.
  6. Micol, Jean-Baptiste; et al. (2014). "Collaborating constitutive and somatic genetic events in myeloid malignancies: ASXL1 mutations in patients with germline GATA2 mutations". Haematologica. 99 (2): 201–203. doi:10.3324/haematol.2013.101303. ISSN 1592-8721. PMC 3912947. PMID 24497555.
  7. 7.0 7.1 7.2 Hahn, Christopher N.; et al. (2011). "Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia". Nature Genetics. 43 (10): 1012–1017. doi:10.1038/ng.913. ISSN 1546-1718. PMC 3184204. PMID 21892162.
  8. 8.0 8.1 8.2 Spinner, Michael A.; et al. (2014). "GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity". Blood. 123 (6): 809–821. doi:10.1182/blood-2013-07-515528. ISSN 1528-0020. PMC 3916876. PMID 24227816.
  9. Pasquet, Marlène; et al. (2013). "High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia". Blood. 121 (5): 822–829. doi:10.1182/blood-2012-08-447367. ISSN 1528-0020. PMC 3714670. PMID 23223431.
  10. Ostergaard, Pia; et al. (2011). "Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome)". Nature Genetics. 43 (10): 929–931. doi:10.1038/ng.923. ISSN 1546-1718. PMID 21892158.
  11. Dickinson, Rachel Emma; et al. (2011). "Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency". Blood. 118 (10): 2656–2658. doi:10.1182/blood-2011-06-360313. ISSN 1528-0020. PMC 5137783. PMID 21765025.
  12. Hsu, Amy P.; et al. (2011). "Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome". Blood. 118 (10): 2653–2655. doi:10.1182/blood-2011-05-356352. ISSN 1528-0020. PMC 3172785. PMID 21670465.
  13. Fisher, Kevin E.; et al. (2017). "Somatic mutations in children with GATA2-associated myelodysplastic syndrome who lack other features of GATA2 deficiency". Blood Advances. 1 (7): 443–448. doi:10.1182/bloodadvances.2016002311. ISSN 2473-9529. PMC 5738979. PMID 29296959.
  14. Wlodarski, Marcin W.; et al. (2016). "Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents". Blood. 127 (11): 1387–1397, quiz 1518. doi:10.1182/blood-2015-09-669937. ISSN 1528-0020. PMID 26702063.
  15. West, Robert R.; et al. (2014). "Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation". Haematologica. 99 (2): 276–281. doi:10.3324/haematol.2013.090217. ISSN 1592-8721. PMC 3912957. PMID 24077845.
  16. Bödör, Csaba; et al. (2012). "Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival". Haematologica. 97 (6): 890–894. doi:10.3324/haematol.2011.054361. ISSN 1592-8721. PMC 3366655. PMID 22271902.
  17. Cuellar-Rodriguez, Jennifer; et al. (2011). "Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency". Blood. 118 (13): 3715–3720. doi:10.1182/blood-2011-06-365049. ISSN 1528-0020. PMC 3186343. PMID 21816832.


*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.