CBFA2, frequently rearranged in leukemia, is not responsible for a familial leukemia syndrome

Legare, RD; Lü, Dan; Gallagher, M. J.; Ho, Ching-Huang; Tan, Xu; Barker, George; Shimizu, Kimiko; Ohki, Masafumi; Lenny, Noel; Hiebert, Scott W.; Gilliland, D. Gary

doi:10.1038/sj.leu.2400852

Cited by 12 publications

(9 citation statements)

References 28 publications

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“…32 Mutations in the RUNX1 Runt domain were not detected in samples from individuals with DS-AMKL, arguing that RUNX1 mutations are not involved in the etiology of AMKL. [32][33][34] However, this finding does not exclude a pathogenic role for increased gene dosage of RUNX1 in the development of AMKL. Other putative leukemic oncogenes on chromosome 21 include the interferon ␣/␤ receptor (IFNAR), cytokine family 2-4 (CFR 2-4), phosphoribosylglycinamide formyltransferase (GART), and the gene with significant homology to MYC and MOS (SON).…”

mentioning

confidence: 55%

Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome

Gurbuxani

Vyas

Crispino

2004

Blood

153

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GATA-1 is the founding member of a transcription factor family that regulates growth and maturation of a diverse set of tissues. GATA-1 is expressed primarily in hematopoietic cells and is essential for proper development of erythroid cells, megakaryocytes, eosinophils, and mast cells. Although loss of GATA-1 leads to differentiation arrest and apoptosis of erythroid progenitors, absence of GATA-1 promotes accumulation of immature megakaryocytes. Recently, we and others have reported that mutagenesis of GATA1 is an early event in Down syndrome (DS) leukemogenesis. Acquired mutations in GATA1 were detected in the vast majority of patients with acute megakaryoblastic leukemia (DS-AMKL) and in nearly every patient with transient myeloproliferative disorder (TMD), a "preleukemia" that may be present in as many as 10% of infants with DS. Although the precise pathway by which mutagenesis of GATA1 contributes to leukemia is unknown, these findings confirm that GATA1 plays an important role in both normal and malignant hematopoiesis. Future studies to define the mechanism that results in the high frequency of GATA1 mutations in DS and the role of altered GATA1 in TMD and DS-AMKL will shed light on the multistep pathway in human leukemia and may lead to an increased understanding of why children with DS are markedly predisposed to leukemia. IntroductionThe incidence of leukemia in children with Down syndrome (DS) is 1 in 100 to 200, which is 10-to 20-fold higher than in children without DS. Although in non-DS children lymphoid neoplasms comprise most of the leukemias arising in this age group, half of the leukemias in DS are myeloid. Children with DS exhibit a 46-fold excess incidence of acute myeloid leukemia (AML), with acute megakaryoblastic leukemia (AMKL) accounting for at least 50% of these cases. 1 In addition to acute leukemia, children with DS are also predisposed to developing the related transient myeloproliferative disorder (TMD). At least 10% of infants with DS develop TMD, a disease in which immature megakaryoblasts accumulate in liver, bone marrow, and peripheral blood; this disorder undergoes spontaneous remission in most cases. [2][3][4] Of note, approximately 30% of DS infants with TMD develop AMKL within 3 years. 1 TMD blasts are morphologically indistinguishable from AMKL blasts, contributing to the hypothesis that the second disease is derived from the first. 5,6 Often the karyotype of the AMKL blasts is more complex than that of the TMD, but contains abnormalities observed in the original TMD clone, consistent with clonal evolution. [7][8][9][10][11] Classified as FAB M7 subtype, these blasts exhibit classical ␣-naphthyl acetate esterase activity with a multifocal punctate cytoplasmic staining pattern that is only partially inhibited by sodium fluoride. 12 Immunophenotyping shows that the blasts express the myeloid markers CD33 and CD13, in addition to at least one platelet-associated antigen (CD36, CD41a, CD41b, or CD61). A proportion of these blasts also express erythroid-specific mRNAs, such as...

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confidence: 55%

Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome

Gurbuxani

Vyas

Crispino

2004

Blood

153

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“…We had previously analysed CBFA2 in pedigree 1 in detail and found no evidence for mutation or deletion 22 . Haplotype analysis using polymorphic markers available at the time, including D21S65, showed no evidence for deletion, and sequence analysis of exons 1-8 amplified from genomic DNA identified no mutations in CBFA2.…”

Section: Intragenic Deletion Of Cbfa2 In Pedigreementioning

confidence: 98%

“…Ribonuclease protection analysis of RNA from lymphoblastoid cell lines of affected and unaffected individuals in pedigree 1 showed no abnormalities in known CBFA2 splice variants. CBFA2 expression was documented in lymphoblastoid cell lines of affected individuals by western-blot analysis, and functional activity of CBFA2 in affected individuals was demonstrated by electrophoretic mobility shift assays 22 . These data demonstrated the presence of at least one functional CBFA2 allele, but did not exclude an intragenic deletion in the other CBFA2 allele, with resultant CBFA2 haploinsufficiency.…”

Section: Intragenic Deletion Of Cbfa2 In Pedigreementioning

confidence: 99%

Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia

et al. 1999

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Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.

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“…12,13 Inherited mutations in RUNX1 causing haploinsufficiency with low level of expression in hematopoietic stem cells cause a syndrome of familial thrombocytopenia and increased susceptibility to leukemia. 14 However, RUNX1 abnormalities have generally not been detected in AMKL and, except for one case report, 15 mutations in RUNX1 have not been found in AMKL associated with DS 13,16 ( Recently, Wechsler et al 17 reported the surprising finding that a gene on chromosome X, GATA1, was mutated in the megakaryoblasts from each of 6 DS patients with AMKL. GATA1 encodes a zinc-finger transcription factor that has been shown to be critical for normal erythroid and megakaryocytic development.…”

Section: Introductionmentioning

confidence: 99%

Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21

Rainis

Bercovich

Strehl

et al. 2003

Blood

279

247

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Patients with Down syndrome (DS) frequently develop 2 kinds of clonal megakaryocytosis: a common, congenital, spontaneously resolving, transient myeloproliferative disorder (TMD) and, less commonly, childhood acute megakaryoblastic leukemia (AMKL). Recently, acquired mutations in exon 2 of GATA1, an X-linked gene encoding a transcription factor that promotes megakaryocytic differentiation, were described in 6 DS patients with AMKL. The mutations prevent the synthesis of the full-length GATA1, but allow the synthesis of a shorter GATA1 protein (GATA1s) that lacks the transactivation domain. To test whether mutated GATA1 is involved in the initiation of clonal megakaryoblastic proliferation or in the progression to AMKL, we screened 35 DS patients with either AMKL or TMD and 7 non-DS children with AMKL for mutations in exon 2 of GATA1. Mutations were identified in 16 of 18 DS patients with AMKL, in 16 of 17 DS patients with TMD, and in 2 identical twins with AMKL and acquired trisomy 21. Analysis revealed various types of mutations in GATA1, including deletion/insertions, splice mutations, and nonsense and missense point mutations, all of which prevent the generation of full-length GATA1, but preserve the translation of GATA1s.We also show that the likely mechanism of generation of GATA1 isoforms is alternative splicing of exon 2 rather than, or in addition to, alternative translation initiation, as was proposed before. These findings suggest that acquired intrauterine inactivating mutations in GATA1 and generation of GATA1s cooperate frequently with trisomy 21 in initiating megakaryoblastic proliferation, but are insufficient for progression to AMKL. (Blood. 2003; 102:981-986)

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CBFA2, frequently rearranged in leukemia, is not responsible for a familial leukemia syndrome

Cited by 12 publications

References 28 publications

Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome

Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome

Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia

Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21

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