Leukemia in a trisomy 21 mosaic: Specific involvement of the trisomic cells

Ferster, Alina; Verhest, Alain; Vamos, Esther; Maertelaere, Emilie De; Otten, Jacques

doi:10.1016/0165-4608(86)90113-5

Cited by 30 publications

(11 citation statements)

References 17 publications

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“…This hypothesis is based on the increased incidence of leukemia in persons with Down syndrome (27) and importantly on the observations that Down syndrome neonates may develop a transient disorder with some features resembling acute leukemia (28)(29)(30). Where there has been mosaicism for trisomy 21 detected in bone marrow cells of patients with this "leukemoid reaction," resolution of the "blasts" occurred in parallel with disappearance of the +21 clone (31,32). It is of interest that the 8;21 translocation breakpoint is located in the segment of chromosome 21 that appears to be responsible for many of the phenotypic features of Down syndrome (10,33,34).…”

Section: Resultsmentioning

confidence: 99%

Isolation of a yeast artificial chromosome spanning the 8;21 translocation breakpoint t(8;21)(q22;q22.3) in acute myelogenous leukemia.

Gao

Erickson

Gardiner

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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The 8;21 translocation is one of the most common specific rearrangements in acute myelogenous leukemia. We have Identified markers (D21S65 and aNotI boundary clone, Not-42, referred to as probe B) flanking the chromosome 21 translocation breakpoint (21q22.3) that demonstrate physical linkage in normal genomic DNA, by using at least three restriction endonucleases (Not I, Sac a, and BssHl), and that are located not more than 250-280 kilobases apart. Pulsed-field gel analysis of DNA from somatic cell hybrids containing the 8;21 translocation chromosomes demonstrates rearrangement of these markers. A 470-kilobase yeast artificial chromosome, YAC-Not-42, has been isolated that contains both probes.Mapping of A subelones constructed from YAC-Not-42 suggests that >95% (25/26 probes tested) of the yeast artificial chromosome DNA is located on the proximal (D21S65) side of the breakpoint. In situ hybridization studies using metaphase chromosomes from five acute myelogenous leukemia patients with the 8;21 trandocation confirmed these results and demonstrated the translocation of probe B to the derivative chromosome 8. A chromosome walk of w39 kilobases from probe B has allowed identification of the breakpoint in DNA from a somatic cell hybrid conining the derivative chromosome 8. Since probe B contains conserved DNA sequences and is in dose proximity to the translocation breakpoint, it may represent a portion of the involved gene on chromosome 21.

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Section: Resultsmentioning

confidence: 99%

Isolation of a yeast artificial chromosome spanning the 8;21 translocation breakpoint t(8;21)(q22;q22.3) in acute myelogenous leukemia.

Gao

Erickson

Gardiner

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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“…The "leukemogenic" role of an additional chromosome 21 was further supported by showing the selective involvement of trisomic cells with leukemia in patients with trisomy 21 mosaicism. 4 In addition, trisomy/polysomy 21and translocations that disrupt the RUNX1 gene on chromosome 21q22 are nonrandom and are among the most frequently acquired chromosomal abnormalities in acute lymphoblastic leukemia (ALL) and acute myelocytic leukemia (AML). [5][6][7] This dosage effect is also seen in patients with a subtype of ALL with intrachromosomal amplification of chromosome 21 encompassing the RUNX1 gene (iAMP21) who have poor outcome.…”

Section: Introductionmentioning

confidence: 99%

Syndromic thrombocytopenia and predisposition to acute myelogenous leukemia caused by constitutional microdeletions on chromosome 21q

Shinawi¹,

Erez²,

Shardy

et al. 2008

Blood

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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. (Blood. 2008; 112:1042-1047)

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“…Similarly, the onset age of six mosaic DS with acute leukaemia was <4 years, and AMKL developed in four of them (Heidemann et al, 1983;Ferster et al, 1986;Simon et al, 1987;Hayashi et al, 1988;Iizuka et al, 1988;Palmer et al, 1995). In contrast, in older children with DS, AML has rarely been seen (Zipursky et al, 1992).…”

Section: Rt-pcr Analysismentioning

confidence: 99%

“…Runt: runt homology domain. It has been shown that the leukaemic clone is of 21 trisomy cell origin in mosaic DS patients developing acute leukaemia (Ferster et al, 1986;Simon et al, 1987;Hayashi et al, 1988;Iizuka et al, 1988). A mosaic DS patient with i(21q) developing TAM suggested that cells with ¹21,þi(21q) might have the same potential for leukaemogenesis as cells with 21 trisomy (Heaton et al, 1981).…”

Section: Rt-pcr Analysismentioning

confidence: 99%

“…An involvement of 21 trisomy in the leukaemogenesis is suggested by the study of mosaic DS developing acute leukaemia. In six mosaic DS with leukaemia, all four patients with cytogenetic analysis showed a leukaemic clone of 21 trisomy cell origin (Heidemann et al, 1983;Ferster et al, 1986;Simon et al, 1987;Hayashi et al, 1988;Iizuka et al, 1988;Palmer et al, 1995).…”

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confidence: 99%

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Acute myelogenous leukaemia with t(8;21) translocation of normal cell origin in mosaic Down's syndrome with isochromosome 21q

Satō¹,

Imaizumi²,

Koizumi³

et al. 1997

Br J Haematol

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Summary. We report a 13-year-old girl with Down's syndrome (DS) having a mosaic karyotype of 46,XX/46,XX, ¹21,þi(21q), who developed acute myelogenous leukaemia (AML) (FAB M1). The t(8;21) translocation generating a AML1/MTG8 chimaeric gene of her blasts was demonstrated by cytogenetic analysis and reverse transcription-polymerase chain reaction. Interestingly, the leukaemic clone with t (8;21) did not have isochromosome 21q, indicating that the blasts were of normal cell origin. These findings suggest that, in older patients with DS, 21 trisomy cells have no greater predisposition to develop AML than normal karyotypic cells.

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Leukemia in a trisomy 21 mosaic: Specific involvement of the trisomic cells

Cited by 30 publications

References 17 publications

Isolation of a yeast artificial chromosome spanning the 8;21 translocation breakpoint t(8;21)(q22;q22.3) in acute myelogenous leukemia.

Isolation of a yeast artificial chromosome spanning the 8;21 translocation breakpoint t(8;21)(q22;q22.3) in acute myelogenous leukemia.

Syndromic thrombocytopenia and predisposition to acute myelogenous leukemia caused by constitutional microdeletions on chromosome 21q

Acute myelogenous leukaemia with t(8;21) translocation of normal cell origin in mosaic Down's syndrome with isochromosome 21q

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