scholarly journals Acute Megakaryoblastic Leukemia Without GATA1 Mutation After Transient Myeloproliferative Disorder in an Infant Without Down Syndrome

2011 ◽  
Vol 29 (9) ◽  
pp. e230-e233 ◽  
Author(s):  
Hiroto Inaba ◽  
Margherita Londero ◽  
Scott H. Maurer ◽  
Mihaela Onciu ◽  
Yubin Ge ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Myeloproliferative Disorder ◽  
Acute Megakaryoblastic Leukemia ◽  
Megakaryoblastic Leukemia ◽  
Transient Myeloproliferative Disorder ◽  
Gata1 Mutation

Activating JAK3 Mutations in Transient Myeloproliferative Disorder and Acute Megakaryoblastic Leukemia Accompanying Down Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1620-1620
Author(s):  
Tomohiko Sato ◽  
Tsutomu Toki ◽  
Rika Kanezaki ◽  
Gang Xu ◽  
Kiminori Terui ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Cell Lines ◽  
Sh2 Domain ◽  
Myeloproliferative Disorder ◽  
Early Event ◽  
Therapeutic Effects ◽  
Acute Megakaryoblastic Leukemia ◽  
Megakaryoblastic Leukemia ◽  
Transient Myeloproliferative Disorder ◽  
Transforming Activity

Abstract Children with Down syndrome (DS) have an approximately 20-fold higher incidence of leukemia than the general population. The majority of leukemia cases associated with DS are acute megakaryoblastic leukemia (AMKL). Although GATA1 mutations have been found in almost all cases of transient myeloproliferative disorder (TMD) “a preleukemia” that may be present in as many as 10% of newborn infants with DS and AMKL accompanying DS (DS-AMKL), GATA1 mutation alone may not be sufficient for development of leukemia. Following identification of acquired activating JAK3 mutations in DS-AMKL, JAK3 mutations have been reported also in TMD patients. However, the frequency and functional consequence of JAK3 mutations in TMD remain unknown. To further understand how JAK3 mutations are involved in the development and/or progression of leukemia in DS, we screened TMD patients and two DS-AMKL cell lines for JAK3 mutation, and examined the functional consequences of these JAK3 mutations. In one out of the two DS-AMKL cell lines, MGS, we identified novel JAK3 mutations (JAK3Q501H mutation in the SH2 domain and JAK3R657Q mutation in the psuedokinase domain in the same allele). JAK3Q501H and JAK3R657Q each constitutively phosphorylates STAT5 and transformes Ba/F3 cells to factor-independent growth, whereas the double mutant (JAK3Q501H and JAK3R657Q) has more potent transforming activity than each mutant. Biochemichal analysis in Ba/F3 cells revealed that the degrees of phosphorylation of STAT5 in the cells transduced with each JAK3 mutant were correlated with its transforming activity. Although we previously identified a JAK3I87T mutation in one of two TMD patients, no JAK3 mutations were detected in another 9 TMD patients. Together with the previous results, we found JAK3 mutations in each of 11 TMD and 11 DS-AMKL patients. Although the number of the patients analyzed was small, these results indicate that there are no significant differences in the frequency of JAK3 mutations between TMD and DS-AMKL. In this study, we showed for the first time that the TMD patient-derived JAK3 mutation was also an activating one. JAK3I87T transformed Ba/F3 cells to factor-independent growth. Treatment with JAK3 inhibitors (WHI-P131 and WHI-P154) resulted in a significant decrease in the growth and viability of Ba/F3 cells expressing each activating JAK3 mutant. These results suggest that the JAK3 activating mutation is an early event during the development of AMKL in DS. Furthermore these results provide a proof-of-principle that JAK3 inhibitor should have therapeutic effects on the AMKL and TMD patients carrying the activating JAK3 mutations.

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

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 888-888 ◽  
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.

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

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 2128-2131 ◽  
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.

scholarly journals Trisomy 21 enhances human fetal erythro-megakaryocytic development

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4503-4506 ◽  
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.

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