In:
Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1699-1699
Abstract:
Abstract 1699 Haploinsufficiency of GATA2 results in three overlapping clinical entities unified by the predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML): i) familial MDS/AML, ii) Emberger syndrome, and iii) an immunodeficiency termed monocytopenia with mycobacterium avium infections (MonoMAC)/ dendritic cell, monocyte, B- and NK-lymphoid deficiency (DCML). All these conditions manifest with a wide heterogeneity of symptoms predominantly affecting the hematologic and immune systems. To investigate the frequency of GATA2 defects in children and adolescents with MDS registered in the retrospective and prospective studies of the European Working Group of MDS and JMML in Childhood (EWOG-MDS), we first identified children from families with MDS/AML affecting multiple individuals, or children with MDS and preexisting lymphedema or immunodeficiency. We measured telomere length in hematopoietic cells to rule out an underlying defect of the telomerase complex, performed SNP-Array analysis, and excluded cases with germline RUNX1 aberrations. We identified heterozygous GATA2 mutations in 11 offspring of 8 distinct pedigrees: 4 previously reported missense mutations affecting the 2nd zinc finger (ZF2) T357A, S447R and R396Q/W; a novel exon 5 skipping mutation c.1018-10_1037del; and one novel nonsense mutation S201X and two novel frameshift mutations S139CfsX45, and V70LfsX114, all resulting in a premature stop codon prior to ZF2. The median age at diagnosis of MDS was 13.6 (11.0–16.9) years. Karyotype abnormalities were detected in 10/11 (91%) children: in 9 at initial presentation and in one during disease progression. Most patients carried the aneuploidies monosomy 7 (−7; n=5), trisomy 8 (+8; n=4), or both (n=1). Additionally, the recurrent translocation +1,der(1;7)(q10;p10) was detected in three patients. Interestingly, in one patient, the initial karyotype 45,XY,-7 transformed at relapse after hematopoietic stem cell transplantation (HSCT) to 46,XY,-7,+8,+21. Two additional patients with hypocellular MDS since adolescence and GATA2 hotspot mutations referred to us carried the aneuploidies −7 or +8, respectively. We next extended our study to children registered to EWOG-MDS in Germany with non-familial MDS and monosomy 7. Unexpectedly 8/51 (16%) patients with −7 carried GATA2 aberrations: 7 missense mutations within ZF2 and a germline 3.6Mb deletion 3q21.2–21.3 encompassing GATA2. In depth review of patient's history identified preexisting features of immunodeficiency as seen on laboratory tests and clinical exam (i.e. generalized verrucosis) in 5 of these 8 patients. The germline status was confirmed in cases where non-hematopoietic specimens were available. The combined analysis of all 21 patients identified additional comorbidities that, to our knowledge, were previously not reported in patients with GATA2-deficiency. These affected the urogenital system (nonselective glomerular proteinuria in one family, vesicoureteral reflux in a single case), neurodevelopmental delay and aggressive behavior in two cases, and ulcerative colitis in 2 families. At diagnosis of MDS, refractory cytopenia of childhood (RCC) was present in 43% of cases, while 33% presented with RAEB, and remaining 24% of patients with RAEBt and myelodysplasia related AML. Following HSCT as first line therapy, 10 of 12 children are alive, while all 4 children treated with AML-like therapy prior to HSCT succumbed. Five patients with RCC are followed closely with a watch and wait regimen. Finally, to study the genetic factors initiating clonal evolution, we subjected selected cases to targeted next generation sequencing of 103 cancer-associated genes. Based on preliminary data, some GATA2-deficient patients carry acquired mutations of genes previously reported in malignant processes (such as ASXL1, RUNX1, TET2, and 14 more genes). In summary, we identified a high frequency of GATA2 mutations among children and adolescents cases with sporadic MDS with monosomy 7 in children and adolescents. Some of these patients had a mild preexisting immunodeficiency. Outcome following HSCT without prior intensive chemotherapy was similar to what can be expected in children with MDS without GATA2 mutations. The genotype-phenotype correlation and mechanisms of clonal evolution are not understood and warrant further studies. Disclosures: No relevant conflicts of interest to declare.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V120.21.1699.1699
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2012
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
