Mosaic trisomy 21 and trisomy 14 as acquired cytogenetic abnormalities without GATA1 mutation in a pediatric non-down syndrome acute megakaryoblastic leukemia

Abstract Abstract 888 Introduction: Pediatric acute megakaryoblastic leukemia (AMKL) occurred in 6.6% (84/1271) of the children enrolled to the AML-BFM98 and 2004 studies. Despite a similar phenotype in morphology and immunophenotype, AMKL shows a heterogenous cytogenetic distribution (normal karyotype 23%, complex karyotype 21%, t(1;22) 9%; MLL-rearrangement 8%; monosomy 7 5%, trisomy 8 5%; other aberrations 29%). Mutations of the hematopoietic transcription factor GATA1 have been identified in almost all children suffering myeloid leukemia of Down syndrome (ML-DS). In addition, GATA1 mutations (GATA1mut) could be identified in children with trisomy 21 mosaic. Here, AMKL without evidence of Down syndrome or Down syndrome mosaic were analyzed for mutations in exon 1, 2 or 3 of the transcription factor GATA1. Patients: Seventy-one children from the AML-BFM Study group (n=51; 2000–2011), the Netherlands (n=10), France (n=3) and Scandinavia (n=7) were included. Within the AML-BFM Group the 51 analyzed patients showed similar characteristics compared to the total cohort of 84 children with AMKL of the AML-BFM 98 and 2004 studies. AMKL was confirmed according to the WHO classification by genetics (t(1;22)); morphology and immunophenotyping. Table 1a) summarizes the patientxs characteristics and b) the cytogenetic results. Methods: For GATA1 mutation screening genomic DNA was amplified by PCR reaction for exon 1, 2, and 3. PCR amplicons were analyzed by direct sequencing or following denaturing high-performance liquid chromatography (WAVE). Results: Seven different GATA1 mutations were detected in 8 children (11.1%; table 2). In all GATA1mut leukemia, a trisomy 21 within the leukemic blasts could be detected. Seven out of these 8 children and all other 64 AMKL patients have been treated with intensive chemotherapy regimens according the study group protocols. The results are given in table 2. All achieved continuous complete remission (CCR; 0.4 to 4.2 years). In one newborn with typical morphology and immunophenotype a GATA1mut associated transient leukemia was supposed. The child achieved CCR (follow-up 6 years). In total, allogeneic stem cell transplantation in 1st CR was performed in 6 children with AMKL (GATA1mut leukemia n=1). Conclusions: GATA1 mutations occurred in 11% of children with AMKL without any symptoms or evidence of trisomy 21 or trisomy 21 mosaic. GATA1 mutations are associated with a trisomy 21 within the leukemic blasts. Although non-response occurred, prognosis was significant better compared to other AMKL. Therefore, analysis of GATA1 mutation in infant AMKL is strongly recommended. Whether treatment reduction similar to ML-DS Down syndrome is feasible needs to be confirmed. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

The biology of pediatric acute megakaryoblastic leukemia

Blood ◽

10.1182/blood-2015-05-567859 ◽

2015 ◽

Vol 126 (8) ◽

pp. 943-949 ◽

Cited By ~ 59

Author(s):

Tanja A. Gruber ◽

James R. Downing

Keyword(s):

Trisomy 21 ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Somatic Mutations ◽

Newly Diagnosed ◽

Acute Megakaryoblastic Leukemia ◽

Pediatric Acute Myeloid Leukemia ◽

Megakaryoblastic Leukemia ◽

Children With Down Syndrome ◽

Gata1 Mutation

Abstract Acute megakaryoblastic leukemia (AMKL) comprises between 4% and 15% of newly diagnosed pediatric acute myeloid leukemia patients. AMKL in children with Down syndrome (DS) is characterized by a founding GATA1 mutation that cooperates with trisomy 21, followed by the acquisition of additional somatic mutations. In contrast, non–DS-AMKL is characterized by chimeric oncogenes consisting of genes known to play a role in normal hematopoiesis. CBFA2T3-GLIS2 is the most frequent chimeric oncogene identified to date in this subset of patients and confers a poor prognosis.

Download Full-text

Incidence and clinical implications of GATA1 mutations in newborns with Down syndrome

Blood ◽

10.1182/blood-2007-01-069542 ◽

2007 ◽

Vol 110 (6) ◽

pp. 2128-2131 ◽

Cited By ~ 76

Author(s):

Sharon R. Pine ◽

Qianxu Guo ◽

Changhong Yin ◽

Somasundaram Jayabose ◽

Charlotte M. Druschel ◽

...

Keyword(s):

Down Syndrome ◽

Somatic Mutations ◽

Acute Megakaryoblastic Leukemia ◽

Megakaryoblastic Leukemia ◽

Intron 1 ◽

Increased Risk ◽

Transient Leukemia ◽

Almost All ◽

Guthrie Cards ◽

Gata1 Mutation

Abstract Somatic mutations in the GATA1 gene are present in almost all cases of Down syndrome (DS)–associated acute megakaryoblastic leukemia (AMKL) and transient leukemia (TL). An in utero origin of the GATA1 mutation suggests it is an early leukemogenic event. To determine the detectable incidence and clinical relevance of GATA1 mutations in DS newborns, we screened Guthrie cards from 590 DS infants for mutations in the GATA1 gene. Twenty-two (3.8%) of 585 evaluable infants harbored a predicted functional GATA1 mutation; 2 were identified exclusively within intron 1. Hispanic newborns were 2.6 times more likely to have a mutated GATA1 gene than non-Hispanics (P = .02). Two newborns with a GATA1 mutation subsequently developed AMKL, and none of the infants without a functional GATA1 mutation were reported to have developed leukemia. In addition to screening for TL, a GATA1 mutation at birth might serve as a biomarker for an increased risk of DS-related AMKL.

Download Full-text

GATA1 mutation negative acute megakaryoblastic leukemia with acquired trisomy 21 presenting with extensive bone marrow necrosis in an adult: A case report and review of the literature

Human Pathology Case Reports ◽

10.1016/j.ehpc.2015.09.003 ◽

2016 ◽

Vol 3 ◽

pp. 12-18

Author(s):

Todd P. Williams ◽

Richard D. Hammer

Keyword(s):

Bone Marrow ◽

Case Report ◽

Trisomy 21 ◽

Review Of The Literature ◽

Acute Megakaryoblastic Leukemia ◽

Bone Marrow Necrosis ◽

Megakaryoblastic Leukemia ◽

Gata1 Mutation

Download Full-text

Fetal origin of the GATA1 mutation in identical twins with transient myeloproliferative disorder and acute megakaryoblastic leukemia accompanying Down syndrome

Blood ◽

10.1182/blood-2003-09-3219 ◽

2004 ◽

Vol 103 (1) ◽

pp. 366-366 ◽

Cited By ~ 40

Author(s):

Akira Shimada ◽

Gang Xu ◽

Tsutomu Toki ◽

Hirokazu Kimura ◽

Yasuhide Hayashi ◽

...

Keyword(s):

Down Syndrome ◽

Myeloproliferative Disorder ◽

Identical Twins ◽

Acute Megakaryoblastic Leukemia ◽

Megakaryoblastic Leukemia ◽

Transient Myeloproliferative Disorder ◽

Fetal Origin ◽

Gata1 Mutation

Download Full-text

GATA1-Centered Genetic Network on Chromosome 21 Drives Down Syndrome Acute Megakaryoblastic Leukemia

Blood ◽

10.1182/blood.v124.21.4310.4310 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4310-4310

Author(s):

Lena Stachorski ◽

Dirk Heckl ◽

Veera Raghavan Thangapandi ◽

Aliaksandra Maroz ◽

Dirk Reinhardt ◽

...

Keyword(s):

Down Syndrome ◽

Progenitor Cells ◽

Candidate Genes ◽

Cell Lines ◽

Trisomy 21 ◽

Fetal Liver ◽

Chromosome 21 ◽

Acute Megakaryoblastic Leukemia ◽

Megakaryoblastic Leukemia

Abstract Children with trisomy 21 (Down syndrome, DS) are predisposed to develop acute megakaryoblastic leukemia (DS-AMKL) as well as the antecedent transient leukemia (DS-TL). Mutations in the transcription factor GATA1 -leading to the exclusive expression of the shorter GATA1 isoform (GATA1s)- are present in nearly all children with DS-AMKL and DS-TL. GATA1s is both essential and sufficient to cause DS-TL in synergy with trisomy 21. To elucidate how the presence of an extra copy of chromosome 21 (hsa21) perturbs fetal hematopoiesis to provide a GATA1s-sensitive background during trisomy 21-associated leukemogenesis, we integrated an RNAi viability screening (512 shRNAmirs against 210 genes on hsa21) and a proteomics approach creating an hsa21 oncogenic network centered on GATA1s. shRNA-mediated knock-down of 42 genes conferred a profound selective growth disadvantage in DS-AMKL cell lines (CMK and CMY). A secondary functional validation screening confirmed 8 genes to specifically affect proliferation, cell viability, apoptosis or differentiation in GATA1s/trisomy-associated leukemia; whereas expression of 9 genes was also essential for proliferation and survival of erythroleukemia (K562) and non-DS-AMKL (M07) cell lines. Gain- and loss-of-function studies of 12 selected candidates (8 GATA1s/trisomy-specific oncogenes plus 4 global oncogenes) in CD34+ hematopoietic stem and progenitor cells (HSPCs) uncovered their regulatory function during megakaryopoiesis, erythropoiesis and myelopoiesis. Knockdown of four genes (USP25, BACH1, U2AF1 and C21orf33) inhibited megakaryocytic and erythroid in vitro differentiation, while enhancing myeloid differentiation. Inversely, ectopic expression of six genes (C21orf33, CHAF1B, IFNGR2, WDR4, RUNX1 or GABPA) resulted in a switch from erythroid to megakaryocytic differentiation. These 12 candidate genes acted synergistically to enhance the self-renewal efficiency of murine fetal liver cells in vitro. Pooled transduction of these genes increased the replating efficiency (more than 5 rounds) of fetal liver HSPCs whereas the colony-forming capacity was lost after second replating in the empty vector control. Further, 9 out of 12 candidate genes were overexpressed in DS-AMKL patient samples (n=23) compared to non-DS-AMKL (n=37; 1.3-fold to 2-fold) underscoring their relevance for the pathogenesis of DS-AMKL. Using an in vivo biotinylation approach to study the protein-protein interaction in DS-AMKL cells, we showed that bioGATA1 is associated with protein-complexes of 10 different hsa21-oncogenes, which are involved in splicing, deubiquitination and transcriptional regulation. Direct interactions with several of these factors are perturbed in N-terminal truncated GATA1s. Thus, we deciphered a complex interactive network on hsa21 around GATA1 positively regulating megakaryopoiesis. Deregulation of this network results in synergistic effects on hematopoietic differentiation, which can promote transformation of GATA1s-mutated fetal hematopoietic progenitor cells. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Trisomy 21 enhances human fetal erythro-megakaryocytic development

Blood ◽

10.1182/blood-2008-05-157859 ◽

2008 ◽

Vol 112 (12) ◽

pp. 4503-4506 ◽

Cited By ~ 81

Author(s):

Stella T. Chou ◽

Joanna B. Opalinska ◽

Yu Yao ◽

Myriam A. Fernandes ◽

Anna Kalota ◽

...

Keyword(s):

Down Syndrome ◽

Trisomy 21 ◽

Clonal Expansion ◽

Myeloproliferative Disorder ◽

Acute Megakaryoblastic Leukemia ◽

Megakaryoblastic Leukemia ◽

Children With Down Syndrome ◽

Enhanced Production ◽

Blood Formation

Abstract Children with Down syndrome exhibit 2 related hematopoietic diseases: transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (AMKL). Both exhibit clonal expansion of blasts with biphenotypic erythroid and megakaryocytic features and contain somatic GATA1 mutations. While altered GATA1 inhibits erythro-megakaryocytic development, less is known about how trisomy 21 impacts blood formation, particularly in the human fetus where TMD and AMKL originate. We used in vitro and mouse transplantation assays to study hematopoiesis in trisomy 21 fetal livers with normal GATA1 alleles. Remarkably, trisomy 21 progenitors exhibited enhanced production of erythroid and megakaryocytic cells that proliferated excessively. Our findings indicate that trisomy 21 itself is associated with cell-autonomous expansion of erythro-megakaryocytic progenitors. This may predispose to TMD and AMKL by increasing the pool of cells susceptible to malignant transformation through acquired mutations in GATA1 and other cooperating genes.

Download Full-text