DNA profiling by arrayCGH in acute myeloid leukemia and myelodysplastic syndromes

Suela, Javier; Álvarez, Sara; Cigudosa, Juan C.

doi:10.1159/000108314

Cited by 42 publications

(27 citation statements)

References 80 publications

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“…These findings are wholly consistent with the reduced clonogenic capacity of treated cells and with the G1/S checkpoint commonly compromised in many tumor cells. These mechanisms allow the repair of DNA damage due to genetic instability, as reported in AML patient cells 47 and in this AML model. 40 Furthermore, ABT-737 was found to profoundly induce stress signals as illustrated by upregulation of phospho-p38 MAPK in both Sca-1 and Mac-1 compartments; hence, concomitant signals emanating via this pathway may represent a viable target in AML.…”

Section: Discussionsupporting

confidence: 52%

BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells

Beurlet

Omidvar

Gorombei

et al. 2013

Blood

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Key Points• BCL-2 homology domain 3 mimetic inhibitor ABT-737 targets leukemia initiating cells and progenitors.• Dephosphorylates RAS signaling proteins and regulates proliferation and differentiation genes detected by gene expression profiling.Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow (BM) blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with cells from treated mice compared with cells from untreated mice, with a reduction of BM blasts, Lin-/Sca-1 1 /c-Kit 1 , and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by technicium-labeled annexin V single photon emission computed tomography and ex vivo by annexin V/7-amino actinomycin D flow cytometry, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, caspase 3 cleavage, and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type (WT) AKT or protein kinase B, extracellular signal-regulated kinase 1/2 and mitogen-activated protein kinase patterns in spleen cells after treatment, which showed reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation, and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells. (Blood. 2013; 122(16):2864-2876

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Section: Discussionsupporting

confidence: 52%

BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells

Beurlet

Omidvar

Gorombei

et al. 2013

Blood

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“…[49][50][51][52][53] CGH-A allowed for a wider application of this technology than very labor-intense chromosomal CGH. 54 The quality of CGH-A-based analysis is limited by the platform on which it is performed and depends on the density of BAC probes, varying from thousands to hundreds of thousands. 25 By comparison, metaphase CGH can only detect lesions of 2 to 10 Mb when present in more than 50% of the cells analyzed.…”

Section: Implications Of Array-based Karyotyping In Hematologic Diseasesmentioning

confidence: 99%

Whole genome scanning as a cytogenetic tool in hematologic malignancies

Maciejewski

Mufti

2008

Blood

125

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Over the years, methods of cytogenetic analysis evolved and became part of routine laboratory testing, providing valuable diagnostic and prognostic information in hematologic disorders. Karyotypic aberrations contribute to the understanding of the molecular pathogenesis of disease and thereby to rational application of therapeutic modalities. Most of the progress in this field stems from the application of metaphase cytogenetics (MC), but recently, novel molecular technologies have been introduced that complement MC and overcome many of the limitations of traditional cytogenetics, including a need for cell culture. Whole genome scanning using comparative genomic hybridization and single nucleotide polymorphism arrays (CGH-A; SNP-A) can be used for analysis of somatic or clonal unbalanced chromosomal defects. In SNP-A, the combination of copy number detection and genotyping enables diagnosis of copy-neutral loss of heterozygosity, a lesion that cannot be detected using MC but may have important pathogenetic implications. Overall, whole genome scanning arrays, despite the drawback of an inability to detect balanced translocations, allow for discovery of chromosomal defects in a higher proportion of patients with hematologic malignancies. Newly detected chromosomal aberrations, including somatic uniparental disomy, may lead to more precise prognostic schemes in many diseases. Routine cytogenetics diagnostics and its limitationsCytogenetic analysis has provided fundamental insights into the molecular pathogenesis of a variety of hematologic disorders. The discovery of the Philadelphia chromosome and other chromosomal aberrations paved the way for the characterization of molecular lesions that lead to phenotypic characteristics of a number of hematologic malignancies. Metaphase cytogenetics (MC) has proven an extremely valuable diagnostic tool, providing definite diagnoses, for example, in the case of balanced pathognomonic translocations in chronic myeloid leukemia (CML), acute promyelocytic leukemia (APL), or core binding factor acute myelogenous leukemias (AMLs). 1,2 Chromosomal aberrations support the cytomorphologic diagnosis and provide prognostic information, for example, in myelodysplastic syndromes (MDSs), [3][4][5] AML with unbalanced translocations, 6-10 multiple myeloma (MM), 11,12 and chronic lymphocytic leukemia (CLL). 13,14 Irrespective of their location, size, and corresponding phenotype, chromosomal defects also represent suitable markers of clonality suggestive of clonal dominance by the malignant clone or, in rare circumstances, of oligoclonality due to a profound depletion of stem cell reserves 15 (Figure 1). Such a scenario explains the occasional occurrence of chromosomal abnormalities in otherwise typical aplastic anemia (AA; M. Wlodarski, L. Gondek, C. L. O'Keefe, R. Tiu, A. Haddad, A. Risitano, J.P.M., manuscript submitted May 2008). Technical advantages and limitations of MCRoutine MC allows for detection of large clonal populations (Ͼ 10% of dividing cells), indicating the presence of sign...

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“…Anyway, it can be assumed that at least 5% of MDS/AML have ETV6 deletion [15,16]. This frequency has been shown to be much higher in association with monosomy 7 [12,17,18].…”

Section: Discussionmentioning

confidence: 99%

A 14.8 Mb 12p Deletion Disrupting ETV6 in a Patient with Myelodysplastic Syndrome

Valetto¹,

Bertini²,

Ciabatti³

et al. 2017

HGCR

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We present on a new case of myelodysplastic syndrome characterized by array Comparative Genomic Hybridization. This technique confirmed the monosomy 7, detected by conventional cytogenetics, and revealed also a deletion on the short arm of chromosome 12. This deletion extends for about 14.8 Mb and breaks ETV6 gene.12p deletion extents in hematological malignancies may vary, but the minimally deleted region almost invariably contains ETV6, that is considered the main candidate tumor suppressor genes within the region for tumor progression. It has been shown that levels of ETV6 were significantly decreased in cases with 12p13 deletions, whereas expression of other genes in the deleted region, like BCL2L14, LRP6, DUSP16 and GPRC5D, did not show any variation, independently of their copy number status. This observation strengthens the fact that ETV6 may play a potential role in the tumorigenesis process. The role of ETV6 in our patient myelodysplastic syndrome is showed by his clinical history and his poor prognosis.

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DNA profiling by arrayCGH in acute myeloid leukemia and myelodysplastic syndromes

Cited by 42 publications

References 80 publications

BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells

BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells

Whole genome scanning as a cytogenetic tool in hematologic malignancies

A 14.8 Mb 12p Deletion Disrupting ETV6 in a Patient with Myelodysplastic Syndrome

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