Germline GATA1s generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype

Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s generating mutations result in congenital anemia in males. We report on two unrelated families harboring germline GATA1s generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy or tetrasomy 21. The leukemia characteristics overlapped those of myeloid leukemia of Down syndrome including age of onset of less than 4 years, unique immunophenotype, complex karyotype, gene expression pattern, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is unique functional cooperatively between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s generating mutations should be included among those associated with familial myelodysplastic syndrome and leukemia predisposition.

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GATA1 Mutations in Transient Leukemia and Myeloid Leukemia in “Down” Syndrome.

Blood ◽

10.1182/blood.v112.11.923.923 ◽

2008 ◽

Vol 112 (11) ◽

pp. 923-923 ◽

Cited By ~ 1

Author(s):

Katarina Reinhardt ◽

Katarina Boehmer ◽

Jan-Henning Klusmann ◽

Manuela Germeshausen ◽

Annette Sander ◽

...

Keyword(s):

Down Syndrome ◽

Trisomy 21 ◽

Myeloid Leukemia ◽

Patient Specific ◽

Exon 2 ◽

Megakaryoblastic Leukemia ◽

Risk Of Death ◽

Splicing Mutations ◽

Transient Leukemia

Abstract Introduction: Newborns with trisomy 21 have a 5 to 10% risk to develop transient leukemia (TL). More than 20% of these infants progress to myeloid leukemia of Down syndrome (ML-DS) within the first 4 years of life. Mutations of the hematopoietic transcription factor GATA1 have been identified in almost all patients with TL and ML-DS. Here we report the biological and follow up data of a large cohort of children with proven GATA1 mutation reported to date either as TL (n=43) or ML-DS (n=28). Results: GATA1 mutations (point mutations, insertion, deletion, duplication; including 45 mutations not yet published) were identified in 42/43 TL (98%) and in 23/28 ML-DS (83%) patients. n age madian gastation week WBC/μl blasts % outcome 1PB: peripheral blood; BM: bone marrow transient leukemia 43 3 days (0 to 57) 37 (31 to 40) 33450 (1000 to 321000) 45 (7 to 91) death n = 3, 7%  ML-DS n = 9, 22% ML-DS 28 1-3 yrs (0.8 to 3) 38 (37 to 38) 4900 (1000 to 160000) PB1 7(1-87)  BM1 24 (4-78) death n = 2, 7%  relapse n=0 In 9 patients multiple mutations were noted in the same clone as confirmed by subcloning. In one patient with TL two different GATA1 mutations were detected in two independent clones. When this patient progressed to ML-DS only the minor clone was present. The majority of the mutations was localized in exon 2 (n=59). Only a few mutations could be found in intron 1 and 2 (n=5) or in exon 3 (n=1). As a result, these mutations led to the introduction of a premature stop codon within exon 2 (n=40), frameshift (n=14), altered splicing (n=7), or lack of an initiation codon (n=4). Interestingly, children with TL and splicing mutations were significantly older at diagnosis than patients with other mutations (day 38 vs. day 3 p <0.05). No differences between mutational types were evident regarding gestational age, white blood cell count, platelet count, hemoglobin levels, or risk of death or ML-DS. In children with a myeloproliferative disease (MPD; n=7) or acute megakaryoblastic leukemia (AMKL; n=1) without stigmata of Down syndrome, GATA1 mutations could be detected. All of them were diagnosed as trisomy 21 mosaic. In this group the frequency of frameshift and altered splice mutations (5/7 vs. 9/36) was significantly higher compared to those with premature stop codons (2/7 vs. 27/36); pFishers exact =0.03). In 20 children (TL n=13, ML-DS n=7) the GATA1 mutant clone has been prospectively monitored by quantitative PCR using patient specific TaqMan probes. Seventeen TL patients showed decreasing minimal residual disease (MRD) levels and became negative (<10−4) during follow-up, whereas three children, who later developed ML-DS, remained positive at all time points. After two treatment elements all ML-DS patients had undetectable levels of GATA1s. After a median follow up of 1.5 years (0.9 to 2 years), no child suffered relapse however, the follow-up is much too short to draw definitive conclusions. Conclusion: In conclusion, we confirmed the high frequency of GATA1 mutations in children with TL or ML-DS. The occurrence of splicing mutations correlated with the age at diagnosis underlining the biologic relevance of the kind of mutation. We demonstrated the feasibility of a leukemia specific monitoring of MRD. As those children with sustaining detectable levels of GATA1s progressed to leukemia, these results might have therapeutic consequences for TL and later for ML-DS. In addition it may serve as a proof of principle for the feasibility of MRD monitoring in other AML-associated mutations. The identification of GATA1s positive MPD and AMKL in children without obvious stigmata of Down syndrome, all confirmed as trisomy 21 mosaic, implicate the necessity of GATA1s diagnostics in all newborn and infants with megakaryoblastic leukemia.

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Collaboration between Activating Mutations in JAK2 and Trisomy 21 in the Acute Lymphoblastic Leukemias of Down Syndrome (DS).

Blood ◽

10.1182/blood.v110.11.lb6.lb6 ◽

2007 ◽

Vol 110 (11) ◽

pp. LB6-LB6 ◽

Cited By ~ 2

Author(s):

Ithamar Ganmore ◽

Dan Bercovich ◽

Linda M. Scott ◽

Anthony R. Green ◽

Giovanni Cazzaniga ◽

...

Keyword(s):

Down Syndrome ◽

B Cell ◽

Survival Data ◽

Trisomy 21 ◽

Childhood Leukemia ◽

Jak2 Mutation ◽

Childhood All ◽

Therapeutic Implications ◽

Constitutive Activation ◽

Increased Risk

Abstract Additional copies of chromosome (chr) 21 are the most common chromosomal aneuploidy in childhood leukemia. Patients with DS have a markedly increased risk for both AML and ALL. Thus trisomy 21 is leukemogenic. DS-AML is uniquely characterized by an acquired mutation in the chr X gene GATA1. The existence of a similar unique collaborating mutation in DS-ALL has been postulated but remained elusive. To identify such mutations, we performed a large mutational screen in 81 diagnostic samples of B cell precursor DS-ALL, stored in central labs of 9 European childhood ALL protocols (representing more than 8000 samples of childhood ALL). Mutations in JAK2 were identified in 16 (19.7%) DS-ALL patients. The mutations are different from those observed in myeloproliferative disorders. In fifteen patients a point mutation resulted in substitution of the conserved Arginine at position 683. In one patient an in-frame insertion caused displacement of the same amino-acid. The mutations cause constitutive activation of JAK2 and are predicted to disrupt a critical interaction between the pseudokinase and the SH2 domains. The mutations are acquired as they do not exist in remission samples. The mutated RNA is expressed. They are unique to DS-ALL as screening of over 300 non DS-ALL, as well as DS-AMKL, has revealed only one instance with a similar mutation. Strikingly, that patient had an ALL with an iso21q abnormality! The clinical presentation and survival data of DS-ALL patients with and without JAK2 mutation is currently analyzed and will be presented in the meeting. Our data demonstrate that novel mutations of JAK2 cooperate with trisomy 21 in at least 20% of ALLs in Down Syndrome. Thus it seems that, like DS-AML, at least 20% of DS-ALLs are different from sporadic childhood leukemias and characterized by unique acquired mutations in genes located outside chr 21 (GATA1 on the chr X and JAK2 on chr 9). Beyond the obvious therapeutic implications, these observations raise the hypothesis that JAK2 is important in B cell development and that constitutive activation of JAK2 in B cell precursors provides a survival advantage in the presence of a germline trisomy 21.

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Association between Inflammatory Conditions and Alzheimer’s Disease Age of Onset in Down Syndrome

Journal of Clinical Medicine ◽

10.3390/jcm10143116 ◽

2021 ◽

Vol 10 (14) ◽

pp. 3116

Author(s):

Florence Lai ◽

Nathaniel Mercaldo ◽

Cassandra M. Wang ◽

Giovi G. Hersch ◽

Herminia Diana Rosas

Keyword(s):

Down Syndrome ◽

Age Of Onset ◽

Vitamin B12 Deficiency ◽

Inflammatory Conditions ◽

Increased Risk ◽

Wide Range ◽

High Prevalence ◽

Autoimmune Conditions ◽

B12 Deficiency ◽

The Relationship

Adults with Down syndrome (DS) have an exceptionally high prevalence of Alzheimer disease (AD), with an earlier age of onset compared with the neurotypical population. In addition to beta amyloid, immunological processes involved in neuroinflammation and in peripheral inflammatory/autoimmune conditions are thought to play important roles in the pathophysiology of AD. Individuals with DS also have a high prevalence of autoimmune/inflammatory conditions which may contribute to an increased risk of early AD onset, but this has not been studied. Given the wide range in the age of AD onset in those with DS, we sought to evaluate the relationship between the presence of inflammatory conditions and the age of AD onset. We performed a retrospective study on 339 adults with DS, 125 who were cognitively stable (CS) and 214 with a diagnosis of AD. Data were available for six autoimmune conditions (alopecia, celiac disease, hypothyroidism, psoriasis, diabetes and vitamin B12 deficiency) and for one inflammatory condition, gout. Gout was associated with a significant delay in the age of AD onset by more than 2.5 years. Our data suggests that inflammatory conditions may play a role in the age of AD onset in DS. Further studies are warranted.

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Investigating the Link Between Trisomy 21 and Acquired Mutations in the GATA1 Gene

The Physician ◽

10.38192/1.6.1.c9 ◽

2019 ◽

Vol 6 (1) ◽

pp. c9

Author(s):

Triya Chakravorty ◽

Irene Roberts

Keyword(s):

Down Syndrome ◽

Acute Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Trisomy 21 ◽

Children With Down Syndrome ◽

Transient Abnormal Myelopoiesis ◽

Increased Risk ◽

Leukaemic Cells ◽

Acute Myeloid

Children with Down syndrome (DS) due to trisomy 21 (T21) are at an increased risk of developing the neonatal preleukaemic disorder transient abnormal myelopoiesis (TAM), which may transform into childhood acute myeloid leukaemia (ML-DS). Leukaemic cells in TAM and ML-DS have acquired mutations in the GATA1 gene. Although it is clear that acquired mutations in GATA1 are necessary for the development of TAM and ML-DS, questions remain concerning the mechanisms of disease.

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Trisomy 21 Driven Pro-Inflammatory Signalling in Fetal Bone Marrow May Play a Role in Perturbed B-Lymphopoiesis and Acute Lymphoblastic Leukemia of Down Syndrome

Blood ◽

10.1182/blood-2019-130180 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1206-1206 ◽

Cited By ~ 1

Author(s):

Sorcha Isabella O'Byrne ◽

Natalina Elliott ◽

Gemma Buck ◽

Siobhan Rice ◽

David O'Connor ◽

...

Keyword(s):

Gene Expression ◽

Bone Marrow ◽

Down Syndrome ◽

Trisomy 21 ◽

Lymphoblastic Leukemia ◽

B Lymphopoiesis ◽

Increased Risk ◽

Cd34 Cells ◽

Inflammatory Signalling

Introduction: Children with Down syndrome (DS) have a markedly increased risk of acute lymphoblastic leukemia (ALL), suggesting that trisomy 21 (T21) has specific effects on hematopoietic stem and progenitor cell (HSPC) biology in early life. Data from human fetal liver (FL) indicates that T21 alters fetal hematopoiesis, causing multiple defects in lympho-myelopoiesis. The impact of T21 on fetal B lymphopoiesis and how this may underpin the increase in ALL is not well known. We have recently found that fetal bone marrow (FBM) rather than FL is the main site of B lymphopoiesis; with a marked enrichment of fetal-specific progenitors (early lymphoid progenitors, ELP and PreProB progenitors) that lie upstream of adult type ProB progenitors (O'Byrne et al, Blood, in press). Previous preliminary data suggested that B progenitors were also reduced in T21 FBM (Roy et al, Blood. 124, 4331). Aim: To dissect putative molecular mechanisms responsible for the defects in T21 FBM B-lymphopoiesis and its association with childhood DS ALL. Methods: Second trimester human FBM and paediatric ALL samples were obtained from the Human Developmental Biology Resource and UK Childhood Leukaemia Cell Bank respectively. Multiparameter flow cytometry/sorting, transcriptome analysis by RNA-sequencing and microarray, and stromal co-culture assays were used to characterize HSPC and mesenchymal stromal cells (MSC) from normal (NM) disomic (n=21-35) and T21 (n=7-12) human FBM; RNASeq was performed on cytogenetically matched non-DS (n=13) and DS ALL (n=7). Results: In contrast to NM FBM, fetal specific progenitors were virtually absent (CD34+CD10-CD19-CD127+ ELP 2.8±0.4% vs. 0.8±0.4% of CD34+ cells) or very severely reduced (CD34+CD10-CD19+ PreProB 12.8±1 vs 2.6±0.7%) in T21 FBM. This was despite a >4-fold increase in the frequency of immunophenotypic HSC (4.2±1.2% vs 0.9±0.2% of CD34+ cells) and similar frequencies of MPP and LMPP in T21 FBM. As in adult BM, the vast majority of B progenitors in T21 FBM were CD34+CD10+CD19+ ProB progenitors with a frequency (28.8±8.3%) similar to NM FBM (30.3±2.3% of CD34+ cells). Thus, T21 causes a severe block in B-progenitor commitment at the LMPP stage, in tandem with a compensatory expansion of ProB progenitors. Consistent with this, T21 FBM HSC, MPP and LMPP had reduced B cell potential in vitro compared to NM FBM in MS5 co-cultures. RNAseq of NM (n=3) and T21 (n=3) FBM HSPC demonstrated global transcriptomic disruption by T21, with increased gene expression in HSC, MPP, LMPP and ProB progenitors. Cell cycle genes were enriched in T21 ProB progenitors. Despite these functional and global gene expression differences, expression of key B-lineage commitment genes was maintained suggesting the defect in B-lymphopoiesis may be secondary to lineage skewing of multipotent progenitors towards a non-B lymphoid fate and/or mediated by extrinsic factors. GSEA pointed to a role for multiple inflammatory pathways in T21 hematopoiesis with dysregulation of IFNα, IL6 and TGFβ signalling pathways in T21 HSC/LMPP. To investigate the role of the T21 microenvironment, we co-cultured NM HSC, MPP and LMPP with T21 or NM primary FBM MSC. T21 FBM MSC (n=3) had reduced capacity to support B cell differentiation in vitro consistent with perturbation of MSC function by T21. Similar to T21 FBM HSPC, transcriptomic analysis of T21 FBM MSC by microarray showed enrichment for IFNα signalling compared to NM; and T21 HSPC and MSC both showed increased gene expression for IFNα receptors IFNAR1 and IFNAR2, which are encoded on chromosome 21. Since IFNα was undetectable by ELISA of conditioned media from NM and T21 MSC, differences in secreted IFNα from MSC are unlikely to fully explain the increased IFN signalling in T21 HSPC and MSC. This suggests that T21 may drive autocrine rather than paracrine IFN signalling in FBM cells. Finally, RNASeq showed perturbed inflammatory signalling in DS ALL compared to non-DS ALL, suggesting a role for T21-driven inflammatory pathways in the biology of DS ALL. Conclusions: These data show that T21 severely impairs B lymphopoiesis in FBM and is associated with expression of proinflammatory gene expression programs in T21 FBM HSPC and MSC and DS ALL. The compensatory expansion of T21 FBM ProB progenitors, through self-renewal or via an alternative differentiation pathway; with concomitant T21-driven proinflammatory signalling may underpin the increased risk of B progenitor ALL in childhood. Disclosures No relevant conflicts of interest to declare.

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Absence of JAK2 V617F Activating Mutations in Children with Acute Megakaryoblastic Leukemia with and without Down Syndrome.

Blood ◽

10.1182/blood.v108.11.4325.4325 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4325-4325

Author(s):

Christian M. Zwaan ◽

Mathilde J.C. Broekhuis ◽

Claudia Langebrake ◽

Bianca F. Goemans ◽

Gertjan J.L. Kaspers ◽

...

Keyword(s):

Down Syndrome ◽

Myeloid Leukemia ◽

Jak2 V617f ◽

Leukemic Cells ◽

Jak2 V617f Mutation ◽

Clinical Samples ◽

Acute Megakaryoblastic Leukemia ◽

Megakaryoblastic Leukemia ◽

Activating Mutations ◽

V617f Mutation

Abstract Activating mutations at codon 617 of the Janus-2 tyrosine kinase (JAK2 V617F) have recently been described in hematological malignancies. In adult acute myeloid leukemia (AML), the reported frequencies vary, and JAK2 V617F mutations have mainly been detected in secondary AML following a myeloproliferative disorder. In adult de novo AML, the mutation was less frequent, and detected in 2/11 (18%) acute megakaryoblastic leukemia (FAB M7) samples (Jelinek et al., Blood 2005), and occasionally in other FAB-types. This prompted us to analyze a cohort of pediatric AML FAB M7 samples for this particular mutation. In children, at least 3 different subsets of AML M7 can be identified: infants with AML M7 characterized by t(1;22)(p13;q13), older children with random cytogenetic aberrations, and myeloid leukemia of Down syndrome (DS ML). DS ML is often preceded by transient myeloproliferative disease (TMD), hence we also screened TMD samples to detect whether JAK2 V617F mutations would be involved in clonal evolution from TMD to DS ML. To exclude germ-line mutations in DS, we tested normal mononuclear bone marrow cells (NBMC) from children with DS. These NBMC were obtained from a sternal aspirate from children undergoing cardiac surgery, after informed consent was obtained. Genomic DNA was harvested from leukemic cells, and JAK2 exon 12, including the intron-flanking regions, was amplified and sequenced to screen for the JAK2 V617F mutation. As a positive control for the JAK2 V617F mutation, we used HEL 92.1.7 cells (an erythroleukemic cell line). In a dilution experiment we could still detect the mutation, using direct sequencing, if 10% HEL/JAK2 mutated cells were mixed with 90% wild-type control cells. We tested 49 samples, comprising of 9 NBMC, 11 TMD, 14 DS-ML M7, 11 non-DS AML M7 and 4 relapsed non-DS AML M7 samples (including 2 initial diagnosis-relapse pairs). The median age of the TMD cohort was 3 days, for DS-ML children 1.9 years (range 0.9–3.8 yrs), and for non-DS AML 1.5 years (range 1.2–13.7 yrs). The median white blood cell count for TMD was 25.8x109/l, for DS-ML 13.8x109/l, and for non-DS AML 12.4x109/l. Cytogenetic data were available in 5/11 non-DS AML cases only, which showed no cases with a t(1;22). No JAK2 V617F mutations were detected in any of the clinical samples. We conclude that the role of JAK2 V617F mutations in pediatric DS and non-DS acute megakaryoblastic leukemia is limited at best. However, we were not able to screen the subgroup of non-DS AML cases with t(1;22).

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Acute Lymphocytic Leukemia and Down Syndrome

Blood ◽

10.1182/blood.v118.21.sci-8.sci-8 ◽

2011 ◽

Vol 118 (21) ◽

pp. SCI-8-SCI-8

Author(s):

Shai Izraeli

Keyword(s):

Down Syndrome ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Mtor Inhibitors ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Aberrant Expression ◽

Childhood All ◽

Increased Risk ◽

The Common

Abstract SCI-8 Children with Down syndrome are at a markedly increased risk for acute lymphoblastic leukemia (DS-ALL). These leukemias are exclusively of the B lymphoid precursor phenotype and occur in a similar age to “common” sporadic ALLs with the striking absence of infant ALL. Recent studies reveal that DS-ALLs are heterogeneous and differ from sporadic ALLs. Only about a fifth of DS-ALLs carry the common cytogenetic aberrations typical to childhood ALL. Genomic rearrangements leading to the expression of a cytokine receptor, CRLF2, are detected in 60% of DS-ALL in comparison with up to 10% of sporadic ALLs. CRLF2 heterodimerizes with Interleukin 7 receptor-α (IL7R) to form the receptor to thymic stromal lymphopoietin (TSLP). This receptor is usually present in macrophages, dendritic cells, and some T lymphocytes and participates in allergic and inflammatory processes. The aberrant expression of the TSLP receptor is DS-ALL (and sporadic ALL) is often associated with additional mutations that cause constitutive activation of the downstream JAK-STAT and mTOR growth signaling pathways. These are either lymphoid specific activating mutations of JAK2 or JAK1 or mutations in CRLF2 or IL7R that cause ligand-independent receptor dimerization. The role of the trisomy in selecting these somatic abnormalities is presently unknown. Clinically, the prognosis of DS-ALL is inferior to sporadic ALL mainly because of increased treatment toxicity. However, recent data suggest that the inferior outcome may also be related to the genetic properties of the leukemic cells and that excessive chemotherapy dose reduction may not be appropriate for these patients. Therefore increased vigilance for infectious complications and optimal supportive care are required during periods of intensive chemotherapy. The common activation of the TSLP signaling pathway in DS-ALLs suggests a future for targeted therapy with JAK and/or mTOR inhibitors. Importantly, research of DS-ALL has proven relevant for the general patient population with ALL, as somatic mutations in the TSLP pathway have been discovered in children and adults with sporadic ALL. A major research challenge is the elucidation of the roles of constitutional and somatic trisomy 21 in leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

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High Frequency of GATA1 Mutations in Childhood Non-Down Syndrome Acute Megakaryoblastic Leukemia

Blood ◽

10.1182/blood.v120.21.888.888 ◽

2012 ◽

Vol 120 (21) ◽

pp. 888-888 ◽

Cited By ~ 1

Author(s):

Katarina Reinhardt ◽

C. Michel Zwaan ◽

Michael Dworzak ◽

Jasmijn D.E. de Rooij ◽

Gertjan Kaspers ◽

...

Keyword(s):

Transcription Factor ◽

Down Syndrome ◽

Trisomy 21 ◽

Mutation Screening ◽

Study Group ◽

Acute Megakaryoblastic Leukemia ◽

Monosomy 7 ◽

Megakaryoblastic Leukemia ◽

Exon 1 ◽

Gata1 Mutation

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.

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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.

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Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983

Blood ◽

10.1182/blood.v99.12.4257 ◽

2002 ◽

Vol 99 (12) ◽

pp. 4257-4264 ◽

Cited By ~ 129

Author(s):

Smita Bhatia ◽

Harland N. Sather ◽

Olga B. Pabustan ◽

Michael E. Trigg ◽

Paul S. Gaynon ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Brain Tumors ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Malignant Neoplasms ◽

Childhood All ◽

Second Neoplasms ◽

Increased Risk ◽

The Impact

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). With improvement in survival, it is important to assess the impact of contemporary risk-based therapies on second neoplasms in ALL survivors. A cohort of 8831 children diagnosed with ALL and enrolled on Children's Cancer Group therapeutic protocols between 1983 and 1995 were observed to determine the incidence of second neoplasms and associated risk factors. The median age at diagnosis of ALL was 4.7 years. The cohort had accrued 54 883 person-years of follow-up. Sixty-three patients developed second neoplasms, including solid, nonhematopoietic tumors (n = 39: brain tumors n = 19, other solid tumors n = 20), myeloid leukemia or myelodysplasia (n = 16), and lymphoma (n = 8). The cumulative incidence of any second neoplasm was 1.18% at 10 years (95% confidence interval, 0.8%-1.5%), representing a 7.2-fold increased risk compared with the general population. The risk was increased significantly for acute myeloid leukemia (standardized incidence ratio [SIR] 52.3), non-Hodgkin lymphoma (SIR 8.3), parotid gland tumors (SIR 33.4), thyroid cancer (SIR 13.3), brain tumors (SIR 10.1), and soft tissue sarcoma (SIR 9.1). Multivariate analysis revealed female sex (relative risk [RR] 1.8), radiation to the craniospinal axis (RR 1.6), and relapse of primary disease (RR 3.5) to be independently associated with increased risk of all second neoplasms. Risk of second neoplasms increased with radiation dose (1800 cGy RR 1.5; 2400 cGy RR 3.9). Actuarial survival at 10 years from diagnosis of second neoplasms was 39%. Follow-up of this large cohort that was treated with contemporary risk-based therapy showed that the incidence of second neoplasms remains low after diagnosis of childhood ALL.

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