Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The t(8;21)(q22:q22) translocation associated with acute myeloid leukemia fuses the AML1/RUNX1 N-terminal portion located on chromosome 21 to most of the ETO/MTG8 gene on chromosome 8. Various investigators have shown that the fusion product AML1-ETO on its own is unable to promote leukemia. Early studies using transgenic mouse models demonstrated that the direct knock-in of the fusion protein expression is embryonic lethal, similar to the AML1 knockout, suggesting that AML1-ETO has a dominant negative role over AML1. Using the embryonic stem cells generated for such studies, we show here that the presence of the fusion product AML1-ETO blocks definitive hematopoiesis in vitro as well, in both one and two step methylcellulose methods of embryonic stem cell hematopoietic differentiation. However, there is a very low occurrence of macrophage colonies, similar to the knock-in mice that display macrophages in cell cultures of yolk sac derived cells. In addition, we show that exogenous expression of AML1 is unable to bypass this AML1-ETO induced definitive hematopoietic block in these cells. This inability is not linked to an inability to reverse gene expression inhibition by AML1-ETO of the PU.1 gene associated with stem cell maintenance and myeloid differentiation. Our results suggest that AML1-ETO functions in a complex competitive manner with AML1 involving transcriptional regulation, protein-protein interactions and post-transcriptional mechanism(s) affecting early embryonic hematopoiesis and possibly leukemogenesis.
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PMID:Inability of RUNX1/AML1 to breach AML1-ETO block of embryonic stem cell definitive hematopoiesis. 1769 41

This study was aimed to investigate the possible effects of cyclic adenosine monophosphate (cAMP) analogue 8-(4-chlorophenylthio) adenosine 3', 5'-cyclic monophosphate (8-CPT-cAMP) on the M(2b) subtype of acute myeloid leukemia (AML-M(2b)) cells. AML-M(2b) is characterized by the non-random chromosome translocation t (8; 21) (q22; q22), through which AML1 (acute myeloid leukemia 1) gene on chromosome 21 is fused with ETO (eight twenty-one) gene on chromosome 8, coding correspondent AML1-ETO fusion protein, which plays a crucial role in the leukemogenesis of AML-M(2b). The AML-M(2b) cell line Kasumi-1 cells were used as an in vitro model. The influences of 8-CPT-cAMP on the proliferation and differentiation of Kasumi-1 cells were evaluated according to cellular morphology, changes in cell surface antigen and cell cycle, as well as nitroblue-tetrazolium (NBT) assay. Meanwhile, semi-quantity RT-PCR and Western blot assay were used to detect the degradation of AML1-ETO fusion protein in Kasumi-1 cells before and after the treatment. The results showed that 8-CPT-cAMP (200 micromol/L) could significantly inhibit cell growth and induce differentiation of Kasumi-1 cells. However, it must be pointed out that 8-CPT-cAMP-induced differentiation in Kasumi-1 is not a typical terminal differentiation. Furthermore, 8-CPT-cAMP exerted little influence on the expression of AML1-ETO fusion gene and its product in Kasumi-1 cells. In conclusion, the 8-CPT-cAMP induced differentiation in Kasumi-1 cells. This results may provide experimental and theoretical basis for the breakthrough of differentiation-induced therapy extended to another leukemia.
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PMID:[cAMP analogue 8-CPT-cAMP inducing differentiation in the M2b subtype of acute myeloid leukemia cell line Kasumi-1]. 1831 98

Several lines of evidence support the presence of dosage-sensitive genes on chromosome 21 that regulate leukemogenesis and hematopoiesis. We report a detailed clinical and molecular characterization of 3 patients with chronic thrombocytopenia caused by distinct constitutional microdeletions involving chromosomal region 21q22.12. The patients exhibited growth restriction, dysmorphic features, and developmental delays. One patient developed acute myelogenous leukemia (AML) at 6 years of age. All 3 deletions included the RUNX1, CLIC6, DSCR, and KCNE1 genes. Our data provide additional support for the role of RUNX1 haploinsufficiency in megakaryopoiesis and predisposition to AML. The leukemic clone had trisomy 21 resulting from duplication of chromosome 21 containing the RUNX1 deletion. This shows that genes other than RUNX1 must also play a role in AML associated with trisomy 21. We recommend that children with syndromic thrombocytopenia have clinical array-comparative genomic hybridization analysis and appropriate cytogenetic studies to facilitate our ability to provide a definitive diagnosis.
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PMID:Syndromic thrombocytopenia and predisposition to acute myelogenous leukemia caused by constitutional microdeletions on chromosome 21q. 1848 7

The 8;21 translocation, which involves the gene encoding the RUNX family DNA-binding transcription factor AML1 (RUNX1) on chromosome 21 and the ETO (MTG8) gene on chromosome 8, generates AML1-ETO fusion proteins. Previous analyses have demonstrated that full-length AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. More recently, we have identified an alternatively spliced form of AML1-ETO, AML1-ETO9a, from t(8;21) acute myeloid leukemia (AML) patient samples. AML1-ETO9a lacks the C-terminal NHR3 and NHR4 domains of AML1-ETO and is highly leukemogenic in the mouse model. Here, we report that the AML1 DNA-binding domain and the ETO NHR2-dimerization domain, but not the ETO NHR1 domain, are critical for the induction of AML by AML1-ETO9a. A region between NHR1 and NHR2 affects latency of leukemogenesis. These results provide valuable insight into further analysis of the molecular mechanism of t(8;21) in leukemogenesis.
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PMID:RUNX1/AML1 DNA-binding domain and ETO/MTG8 NHR2-dimerization domain are critical to AML1-ETO9a leukemogenesis. 1903 4

Down syndrome (DS) children have a unique genetic susceptibility to develop leukemia, in particular, acute megakaryocytic leukemia (AMkL) associated with somatic GATA1 mutations. The study of this genetic susceptibility with the use of DS as a model of leukemogenesis has broad applicability to the understanding of leukemia in children overall. On the basis of the role of GATA1 mutations in DS AMkL, we analyzed the mutational spectrum of GATA1 mutations to begin elucidating possible mechanisms by which these sequence alterations arise. Mutational analysis revealed a predominance of small insertion/deletion, duplication, and base substitution mutations, including G:C>T:A, G:C>A:T, and A:T>G:C. This mutational spectrum points to potential oxidative stress and aberrant folate metabolism secondary to genes on chromosome 21 (eg, cystathionine-beta-synthase, superoxide dismutase) as potential causes of GATA1 mutations. Furthermore, DNA repair capacity evaluated in DS and non-DS patient samples provided evidence that the base excision repair pathway is compromised in DS tissues, suggesting that inability to repair DNA damage also may play a critical role in the unique susceptibility of DS children to develop leukemia. A model of leukemogenesis in DS is proposed in which mutagenesis is driven by cystathionine-beta-synthase overexpression and altered folate homeostasis that becomes fixed as the ability to repair DNA damage is compromised.
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PMID:Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome. 1963 2

The patterns of malignancies in Down syndrome (DS) are unique and highlight the relationship between chromosome 21 and cancer. DS children have a approximately 10- to 20-fold higher risk for developing acute lymphoblastic leukemia and acute myeloid leukemia (AML), as compared with non-DS children, although they do not have a uniformly increased risk of developing solid tumors. DS children with acute lymphoblastic leukemia frequently experience higher levels of treatment-related toxicity and inferior event-free survival rates, as compared with non-DS children. DS children also develop AML with unique features and have a 500-fold increased risk of developing the AML subtype, acute megakaryocytic leukemia (AMkL; M7). Nearly 10% of DS newborns are diagnosed with a variant of AMkL, the transient myeloproliferative disorder, which can resolve spontaneously without treatment; event-free survival rates for DS patients with AMkL ranges from 80% to 100%, in comparison with <30% for non-DS children with AMkL. In addition, somatic mutations of the GATA1 gene have been detected in nearly all DS TMD and AMkL cases and not in leukemia cases in non-DS children. GATA1 mutations are key factors linked to both leukemogenesis and the high cure rates of DS AMkL patients. Identifying the mechanisms that account for the high event-free survival rates of DS AMkL patients may ultimately improve AML treatment as well. Examining leukemogenesis in DS children may identify factors linked to the general development of childhood leukemia and lead to potential new therapeutic strategies to fight this disease.
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PMID:Down syndrome and malignancies: a unique clinical relationship: a paper from the 2008 william beaumont hospital symposium on molecular pathology. 1971 Mar 97

Trisomy of human chromosome 21 (Hsa21) results in Down syndrome (DS), a disorder that affects many aspects of physiology, including hematopoiesis. DS children have greatly increased rates of acute lymphoblastic leukemia and acute megakaryoblastic leukemia (AMKL); DS newborns present with transient myeloproliferative disorder (TMD), a preleukemic form of AMKL. TMD and DS-AMKL almost always carry an acquired mutation in GATA1 resulting in exclusive synthesis of a truncated protein (GATA1s), suggesting that both trisomy 21 and GATA1 mutations are required for leukemogenesis. To gain further understanding of how Hsa21 contributes to hematopoietic abnormalities, we examined the Tc1 mouse model of DS, which carries an almost complete freely segregating copy of Hsa21, and is the most complete model of DS available. We show that although Tc1 mice do not develop leukemia, they have macrocytic anemia and increased extramedullary hematopoiesis. Introduction of GATA1s into Tc1 mice resulted in a synergistic increase in megakaryopoiesis, but did not result in leukemia or a TMD-like phenotype, demonstrating that GATA1s and trisomy of approximately 80% of Hsa21 perturb megakaryopoiesis but are insufficient to induce leukemia.
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PMID:Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome. 2015 21

Children with trisomy 21/Down syndrome (DS) are at high risk to develop acute megakaryoblastic leukemia (DS-AMKL) and the related transient leukemia (DS-TL). The factors on human chromosome 21 (Hsa21) that confer this predisposing effect, especially in synergy with consistently mutated transcription factor GATA1 (GATA1s), remain poorly understood. Here, we investigated the role of Hsa21-encoded miR-125b-2, a microRNA (miRNA) overexpressed in DS-AMKL/TL, in hematopoiesis and leukemogenesis. We identified a function of miR-125b-2 in increasing proliferation and self-renewal of human and mouse megakaryocytic progenitors (MPs) and megakaryocytic/erythroid progenitors (MEPs). miR-125b-2 overexpression did not affect megakaryocytic and erythroid differentiation, but severely perturbed myeloid differentiation. The proproliferative effect of miR-125b-2 on MEPs accentuated the Gata1s mutation, whereas growth of DS-AMKL/TL cells was impaired upon miR-125b repression, suggesting synergism during leukemic transformation in GATA1s-mutated DS-AMKL/TL. Integrative transcriptome analysis of hematopoietic cells upon modulation of miR-125b expression levels uncovered a set of miR-125b target genes, including DICER1 and ST18 as direct targets. Gene Set Enrichment Analysis revealed that this target gene set is down-regulated in DS-AMKL patients highly expressing miR-125b. Thus, we propose miR-125b-2 as a positive regulator of megakaryopoiesis and an oncomiR involved in the pathogenesis of trisomy 21-associated megakaryoblastic leukemia.
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PMID:miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia. 2019 40

Down syndrome is associated with a markedly increased risk of childhood leukemias, and identification of chromosome 21 sequences that have a role in leukemogenesis may provide insights into critical pathways and suggest targets for therapy and prevention. A study in this issue of Oncogene, defines human chromosome 21 sequences that alter hematopoiesis and induce expression of leukemia-associated markers.
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PMID:Trisomy 21 leukemias: finding the hits that matter. 2069 43

Acute leukemias in children with Down syndrome (DS) are characterized by unique clinical and biological features. Notable among DS children with acute myeloid leukemia (AML), is the high frequency of the acute megakaryocytic leukemia (AMkL) subtype, which uniformly harbor somatic mutations in the transcription factor GATA1 gene. DS patients with AML, and in particular AMkL, have event-free survival rates of 80-100% in contrast to event-free survival rates of less than 35% for non-DS children with AMkL. DS children with acute lymphoblastic leukemia have a more heterogeneous disease, with approximately 30% of the patients having somatic JAK2 mutations, heightened methotrexate sensitivity and higher rates of treatment-related toxicities. These features highlight a striking relationship between genes localized to chromosome 21, leukemogenesis and sensitivity to leukemia chemotherapy agents.
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PMID:Unique clinical and biological features of leukemia in Down syndrome children. 2108 61


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