Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1993-05-13
2001-01-16
Zitomer, Stephanie W. (Department: 1655)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024310, C536S024330, C435S006120
Reexamination Certificate
active
06175000
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to analytical and diagnostic methods, as well as novel polynucleotide sequences and peptides encoded thereby. In a particular aspect, this invention relates to methods for identifying the existence of specific chromosomal aberrations in the genome of a host subject. In another aspect, this invention relates to methods for diagnosing actual or nascent disease states employing the information obtained, applying the invention technique(s) for the determination of the presence of chromosomal aberrations.
BACKGROUND OF THE INVENTION
Specific chromosome translocations are characteristic of some leukaemias and solid tumors, and may lead to malignant transformation through the activation or aberrant expression of breakpoint-associated genes [Berger et al., Leukemia Res. Vol. 6:17-26 (1982)]. For example, rearrangements involving human chromosome region 11 q23 are observed in acute leukaemias, especially t(4;11), t(1;11), and t(11;19) in acute lymphoid leukaemias (ALL) [see, for example, Mazo et al., Proc. Natl. Acad. Sci. USA Vol. 87:2112-2116 (1990)]; and t(1;11) t(2;11), t(6;11), t(9;11), t(10;11), t(11;17) and t(X;11) in acute myeloid leukaemia (AML) [see, for example, Sait et al., Cancer Genet. Cytogenet. Vol. 24:181-183 (1987), Feder et al., Cancer Genet. Cytogenet. Vol. 15:143-150), Derre et al., Gene Chromosom. Cancer Vol. 2:341-344 (1990, Hagemeijer et al., Cancer Genet. Cytogenet. Vol. 5:95-105 (1982), and Pui et al., Blood Vol. 69:1289-1293 (1987)].
The frequency of 11 q23 abnormalities is particularly high in leukaemia occurring in infants, accounting for more than 75% of acute leukaemias in those under 12 months of age [see, for example, Abe et al., Cancer Genet. Cytogenet. Vol. 9:139-144 (1983), Chuu et al., Am. J. Hematol. Vol. 34:246-251 (1990), and Gibbons et al., Br. J. Hematol. Vol. 74:264-269 (1990)]. Leukaemia cells isolated from ALLs with the t(4;11) translocation typically exhibit monocytic as well as lymphocytic characteristics, leading to speculation that the gene or genes located at the translocation breakpoint might affect development of an early lymphoid/myeloid precursor stem cell [see Rowley et al., Proc. Natl. Acad. Sci. USA Vol. 87:9358-9362 (1990)].
Previous studies have localized the t(4;11) breakpoint and the t(9;11) breakpoint associated with acute monoblastic (M4-AML) or myelomonocytic (M5-AMML) leukaemias to the same 5.8 kb region of chromosome 11 q23 [see Cimino et al., Cancer Research Vol. 51:6712-6714 (1991)]. Recently, other studies have identified large 11 to 12 kb transcripts arising from the region of the t(4;11) (q21:q23) translocation [see, for example, Ziemin-van der poel et al., Proc. Natl. Acad. Sci. USA Vol. 88:10735-10739 (1991), and Cimino et al., Cancer Research Vol. 52:3811-3813 (1992)].
Accordingly, since consistent chromosome translocations have been associated with a number of human malignancies (including leukaemias, lymphomas and solid tumors), and such translocations may be intimately involved in the molecular pathogenesis of the associated disorders, the development of rapid and effective methods to analyze for the presence of chromosomal aberrations related to such disease states (e.g., translocations involving a chromosomal site of interest) would provide a useful aid in the diagnosis of actual or nascent disease states.
BRIEF DESCRIPTION OF THE INVENTION
In order to isolate the loci of chromosome 11 involved in acute lymphoid leukaemias (ALL) and acute myeloid leukaemias (AML), as well as other leukaemia-associated breakpoints believed to be present on chromosome 11, extensive physical mapping of chromosome 11 q23 was carried out by the isolation of yeast artificial chromosomes. In the course of construction of a physical map of human chromosome region 11 q23, the region containing the t(4;11) and t(9;11) translocation breakpoint was cloned, and genes whose expression is affected by chromosome rearrangement were identified. Presented herein is a physical map and the DNA sequence of the translocation breakpoint, as well as the identity of the sequences in the immediate proximity of this breakpoint.
The DNA sequence of the breakpoint region shows that one of the transcripts of the DNA isolated in accordance with the present invention is interrupted as a result of translocation, and corresponds to a human gene homologous to the
Drosophila trithorax
(trx) gene product.
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Djabali Malek
Evans Glen A.
Parry Pauline
Selleri Licia
Gray Cary Ware & Freidenrich
Reiter Stephen E.
The Salk Institute for Biological Studies
Zitomer Stephanie W.
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