Biology and outcome of childhood acute megakaryoblastic leukemia: A single institution's experience

Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Blood (Impact Factor: 10.45). 06/2001; 97(12):3727-32. DOI: 10.1182/blood.V97.12.3727
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To describe the clinical and biologic features of pediatric acute megakaryoblastic leukemia (AMKL) and to identify prognostic factors, experience at St Jude Children's Research Hospital was reviewed. Of 281 patients with acute myeloid leukemia treated over a 14-year period, 41 (14.6%) had a diagnosis of AMKL. Six patients had Down syndrome and AMKL, 6 had secondary AMKL, and 29 had de novo AMKL. The median age of the 22 boys and 19 girls was 23.9 months (range, 6.7-208.9 months). The rate of remission induction was 60.5%, with a 48% rate of subsequent relapse. Patients with Down syndrome had a significantly higher 2-year event-free survival (EFS) estimate (83%) than did other patients with de novo AMKL (14%) or with secondary AMKL (20%; P < or =.038). Among patients who had de novo AMKL without Down syndrome, 2-year EFS was significantly higher after allogeneic bone marrow transplantation (26%) than after chemotherapy alone (0%; P =.019) and significantly higher when performed during remission (46%) than when performed during persistent disease (0%; P =.019). The 5-year survival estimates were significantly lower for de novo AMKL (10%) than for other forms of de novo AML (42%; P <.001). Treatment outcome is very poor for patients with AMKL in the absence of Down syndrome. Remission induction is the most important prognostic factor. Allogeneic transplantation during remission offers the best chance of cure; in the absence of remission, transplantation offers no advantage over chemotherapy alone. (Blood. 2001;97:3727-3732)

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    • "Particularly children with Down syndrome (DS), i.e. trisomy 21, have a 400-fold increased risk [11] to develop acute megakaryoblastic leukemia (AMKL). Patients with DS-AMKL have an excellent prognosis with 5-year overall survival rates of about 80%, while non-DS-AMKL patients have poor survival rates of only 14% to 34% despite high intensity chemotherapy [12,13]. The molecular mechanisms underlying this AML subtype remain incompletely understood. "
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    ABSTRACT: Background Long non-coding RNAs (lncRNAs) are recognized as pivotal players during developmental ontogenesis and pathogenesis of cancer. The intronic microRNA (miRNA) clusters miR-99a ~ 125b-2 and miR-100 ~ 125b-1 promote progression of acute megakaryoblastic leukemia (AMKL), an aggressive form of hematologic cancers. The function of the lncRNA hostgenes MIR99AHG (alias MONC) and MIR100HG within this ncRNA ensemble remained elusive. Results Here we report that lncRNAs MONC and MIR100HG are highly expressed in AMKL blasts. The transcripts were mainly localized in the nucleus and their expression correlated with the corresponding miRNA clusters. Knockdown of MONC or MIR100HG impeded leukemic growth of AMKL cell lines and primary patient samples. The development of a lentiviral lncRNA vector to ectopically express lncRNAs without perturbing their secondary structure due to improper termination of the viral transcript, allowed us to study the function of MONC independent of the miRNAs in cord blood hematopoietic stem and progenitor cells (HSPCs). We could show that MONC interfered with hematopoietic lineage decisions and enhanced the proliferation of immature erythroid progenitor cells. Conclusions Our study reveals an unprecedented function of lncRNAs MONC and MIR100HG as regulators of hematopoiesis and oncogenes in the development of myeloid leukemia.
    Molecular Cancer 07/2014; 13(1):171. DOI:10.1186/1476-4598-13-171 · 4.26 Impact Factor
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    • "Hence, studies examining the basis for the relative chemotherapy resistance of these subgroups may lead to improvements in therapy. The significantly higher cure rates of DS AMKL patients, who almost uniformly harbor somatic mutations in the GATA1 gene, suggested that GATA1 may play a critical role in chemotherapy response and resistance [3,5–9]. This is also supported by studies which established an association between high expression levels of GATA1 and a poorer prognosis in adult AML [12,13]. "
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    ABSTRACT: It has been previously shown that acute myeloid leukemia (AML) patients with higher levels of GATA1 expression have poorer outcomes. Furthermore, pediatric Down syndrome (DS) patients with acute megakaryocytic leukemia (AMKL), whose blast cells almost universally harbor somatic mutations in exon 2 of the transcription factor gene GATA1, demonstrate increased overall survival relative to non-DS pediatric patients, suggesting a potential role for GATA1 in chemotherapy response. In this study, we confirmed that amongst non-DS patients, GATA1 transcripts were significantly higher in AMKL blasts compared to blasts from other AML subgroups. Further, GATA1 transcript levels significantly correlated with transcript levels for the anti-apoptotic protein Bcl-xL in our patient cohort. ShRNA knockdown of GATA1 in the megakaryocytic cell line Meg-01 resulted in significantly increased cytarabine (ara-C) and daunorubicin anti-proliferative sensitivities and decreased Bcl-xL transcript and protein levels. Chromatin immunoprecipitation (ChIP) and reporter gene assays demonstrated that the Bcl-x gene (which transcribes the Bcl-xL transcripts) is a bona fide GATA1 target gene in AMKL cells. Treatment of the Meg-01 cells with the histone deacetylase inhibitor valproic acid resulted in down-regulation of both GATA1 and Bcl-xL and significantly enhanced ara-C sensitivity. Furthermore, additional GATA1 target genes were identified by oligonucleotide microarray and ChIP-on-Chip analyses. Our findings demonstrate a role for GATA1 in chemotherapy resistance in non-DS AMKL cells, and identified additional GATA1 target genes for future studies.
    PLoS ONE 07/2013; 8(7):e68601. DOI:10.1371/journal.pone.0068601 · 3.23 Impact Factor
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    • "AMKL is divided into two subgroups: AMKL arising in patients with Down syndrome (DS-AMKL), and leukemia arising in patients without Down syndrome (non-DS- AMKL). Although DS-AMKL patients have an excellent prognosis with an $80% survival, non-DS-AMKL patients do not fare as well, with a reported survival of only 14%–34% despite highintensity chemotherapy (Athale et al., 2001; Barnard et al., 2007; Creutzig et al., 2005). With the exception of the t(1;22) seen in infant non-DS-AMKL, little is known about the molecular lesions that underlie this leukemia subtype (Carroll et al., 1991; Lion et al., 1992; Ma et al., 2001; Mercher et al., 2001). "
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    ABSTRACT: To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.
    Cancer cell 11/2012; 22(5):683-97. DOI:10.1016/j.ccr.2012.10.007 · 23.52 Impact Factor
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