Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-02-19
2002-04-09
Jones, W. Gary (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200
Reexamination Certificate
active
06368791
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is diagnosis of and therapy for leukemia.
BACKGROUND OF THE INVENTION
Leukemias including, but not limited to, acute leukemias such as acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are among the most common malignancies in children. Myelodysplastic syndrome is a designation for a group of syndromes similar to preleukemia (see, e.g.
The Merck Manual,
16th ed., Berkow et al., Eds., Merck Research Laboratories, Rahway, N.J., pp. 1243-1245). Leukemias are also a serious cause of morbidity and mortality among adult humans, although MLL gene translocations are present in perhaps only a small proportion of adult acute leukemias. The incidences of ALL and AML in the United States are, respectively, 20 and 10.6 per million individuals per year in infants less than one year old. The aggressiveness with which a leukemia is treated depends, in part, on whether the leukemia has as its genesis a rearrangement of a portion of a chromosome at one or more particular sites. Some translocations may be detected by karyotype analysis, and others cannot be detected by such analysis.
Translocation of the MLL gene (which is alternately designated ALL-1, Htrx1, or HRX) at chromosome band 11q23 is associated with most cases of ALL which occur during infancy and with most monoblastic variants of AML which occur during the first four years of life (Cimino et al., 1993, Blood 82:544-546; Pui et al., 1995, Leukemia 9:762-769; Hilden et al., 1995, Blood 86:3876-3882; Chen et al., 1993, Blood 81:2386-2393; Martinez-Climent et al., 1993, Leukemia 9:1299-1304). About five percent of de novo cases of adult acute leukemia and most DNA topoisomerase II inhibitor-related leukemias are associated with similar translocations (Pui et al., 1995, supra; Martinez-Climent et al., 1993, supra; Raimondi, 1993, Blood 81:2237-2251; Felix et al., 1995, supra).
The MLL gene is 90 kilobases long, comprises 36 exons, and encodes a 3969 amino acid residue protein (Rasio et al., 1996, Cancer Res. 56:1766-1769). The MLL gene is believed to be involved in hematopoiesis and leukemogenesis. The MLL gene product contains several structural motifs important in the regulation of transcription (Domer et al., 1993, Proc. Natl. Acad. Sci. USA 90:7884-7888; Djabali et al., 1992, Nature Genet. 2:113-118; Gu et al., 1992, Cell 71:701-708; Tkachuk et al., 1992, Cell 71:691-700; Ma et al., 1993, Proc. Natl. Acad. Sci. USA 90:6350-6354) and functions as a positive regulator of Hox gene expression (Yu et al., 1995, Nature 378:505-508). Translocation of the MLL gene at chromosome band 11q23 disrupts an 8.3 kilobase breakpoint cluster region (ber) which is interposed between exons 5 and 11 of MLL. Approximately thirty different translocation partner genes of MLL have been recognized (Martinez-Climent et al., 1993, supra; Raimondi, Blood 81:2237-2251; Felix et al., 1995, Blood 85:3250-3256). Many of these partner genes have not been cloned or characterized.
MLL gene translocations may be detected by karyotype analysis as terminal 11q23 deletions (Shannon et al., 1993, Genes Chromosomes Cancer 7:204-208; Prasad et al., 1993, Cancer Res. 53:5624-5628; Yamamoto et al., 1994, Blood 83:2912-2921). About one third of ALL cases are associated with MLL rearrangements that cannot be detected by karyotype analysis. (Sorenson et al., 1992, Blood 80:255a; Schichman et al., 1994, Proc. Natl. Acad. Sci. USA 91:6236-6239; Schichman et al., 1994, Cancer Res. 54:4277-4280).
Sites of chromosome rearrangement (hereinafter, “breakpoint regions”) have been localized to introns within the bcr of MLL in several de novo cases of leukemia (Gu et al., 1992, Proc. Natl. Acad. Sci. USA 89:10464-10468; Negrini et al., 1993, Cancer Res. 53:4489-4492; Domer et al., 1993, Proc. Natl. Acad. Sci. USA 90:7884-7888; Corral et al., 1993, Proc. Natl. Acad. Sci. USA 90:8538-8542; Gu et al., 1994, Cancer Res. 54:2327-2330). The location of breakpoint regions within MLL and the identity of the nucleotide sequences located at such breakpoint regions are believed to vary according to etiology and pathogenesis of the leukemia. Fewer than half of the about thirty known MLL translocation partner genes have been cloned and identified, although for many of these partner genes, only partial or cDNA sequences are known.
One determinant of the location of a breakpoint region may be the nucleotide sequence preference attributable to either DNA topoisomerase II or a complex comprising DNA topoisomerase II and an agent which interacts with DNA topoisomerase II (Liu et al., 1991, In:
DNA Topoisomerases in Cancer
, Oxford University Press, New York, pp. 13-22; Ross et al., 1988, In:
Important Advances in Oncology
, pp.65-79; Pommier et al., 1991, Nucl. Acids Res. 19:5973-5980; Pommier, 1993, Cancer Chemother. Pharmacol. 32:103-108). For example, epipodophyllotoxins form a complex with DNA and DNA topoisomerase II, whereby chromosomal breakage can be effected at the site of complex formation (Corbett et al., 1993, Chem. Res. Toxicol. 6:585-597). Epipodophyllotoxins and other DNA topoisomerase II inhibitors have been associated with leukemias characterized by heterogenous translocations throughout the bcr of MLL at chromosome band 11q23 (Pui et al., 1991, N. Engl. J. Med. 325:1682-1687; Pui et al., 1990 Lancet 336:417-421; Winick et al., J. Clin. Oncol. 11:209-217; Broeker et al., 1996, Blood 87:1912-1922; Felix et al., 1993, Cancer Res. 53:2954-2956; Felix et al., 1995, Blood, 85:3250-3256; Pedersen-Bjergaard, 1992, Leukemia Res. 16:61-65; Pedersen-Bjergaard, 1991, Blood 78:1147-1148).
DNA topoisomerase II catalyzes transient double-strand breakage and religation of genomic DNA, and is involved in regulating DNA topology by relaxation of supercoiled genomic DNA. It is believed that agents which interact with DNA topoisomerase II and which are associated with leukemias inhibit the ability of DNA topoisomerase II to catalyze religation following double-strand breakage. One suggested model for translocations involving MLL entails DNA topoisomerase II-mediated chromosome breakage within the bcr, followed by fusion of DNA free ends from different chromosomes mediated by cellular DNA repair mechanisms (Felix et al., 1995, Cancer Res. 55:4287-4292). Although not strictly inhibitors in the enzymatic sense, epipodophyllotoxins are designated DNA topoisomerase II inhibitors because they decrease the rate of chromosomal religation catalyzed by DNA topoisomerase II and stabilize the DNA topoisomerase II-DNA covalent intermediate (Chen et al., 1994, Annu. Rev. Pharmacol. Toxicol. 84:191-218; Osheroff, 1989, Biochemistry 28:6157-6160; Chen et al., 1984, J. Biol. Chem. 259:13560-13566; Wang et al., 1990, Cell 62:403-406; Long et al., 1985, Cancer Res. 45:3106-3112; Epstein, 1988, Lancet 1:521-524; Osheroff et al., 1991, In:
DNA Topoisomerases in Cancer
, Potmesil et al., Eds., Oxford University Press, New York, pp. 230-239).
Chromatin structure and scaffold attachment regions may also affect the location of a breakpoint within bcr (Broeker et al., 1996, Blood 87:1912-1922).
Abasic sites are produced by oxidative DNA damage, ionizing radiation, alkylating agents, and spontaneous DNA hydrolysis (Kingma et al., 1995, J. Biol. Chem. 270:21441-21444). Abasic sites are the most common form of spontaneous DNA damage. Abasic sites resulting from exposure to environmental toxins or spontaneous abasic sites may be important mediators of leukemogenesis and provide another explanation of how chromosomal breakage is initiated in leukemia in infants (Kingma et al., 1997, Biochemistry 36:5934-5939), because abasic sites increase DNA topoisomerase II-mediated breakage.
Panhandle PCR methods have been described, and can be used to amplify genomic DNA having a nucleotide sequence comprising a known sequence which flanks an unknown sequence located 3′ with respect to the known sequence (Jones et al., 1993, PCR Meth. Applicat. 2:197-203; U.S. Pat. No. 5,411,875). The panhandle PCR methods comprise generation of a single-stranded DNA having a sequence compris
Felix Carolyn A.
Jones Douglas H.
Rappaport Eric
Dann Dorfman Herrell and Skillman
Souaya Jehanne
The Children's Hospital of Philadelphia
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