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2007/050706 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date national Publication Number 3 May 2007 (03.05.2007) 2007/050706 A2 (51) International Patent Classification: Hall, Columbia, Missouri 65211-2015 (US). TAYLOR, C12Q 1/68 (2006.01) Kristen [US/US]; 475 McReynolds Hall, Columbia, Missouri 6521 1-2015 (US). LAUX, Doug [US/US]; 475 (21) International Application Number: McReynolds Hall, Columbia, Missouri 6521 1-2015 (US). PCT/US2006/041670 DUFF, Dieter [US/US]; 475 McReynolds Hall, Columbia, Missouri 6421 1-2015 (US). JUYAN, Guo [US/US]; 475 (22) International Filing Date: 27 October 2006 (27.10.2006) McReynolds Hall, Columbia, Missouri 6521 1-2015 (US). (25) Filing Language: English (74) Agents: DAVISON, Barry, L. et al; 2600 Century Square, 1501 Fourth Avenue, Seattle, Washington (26) Publication Language: English 98101-1688 (US). (30) Priority Data: (81) Designated States (unless otherwise indicated, for every 60/731,040 27 October 2005 (27.10.2005) US kind of national protection available): AE, AG, AL, AM, 60/733,648 4 November 2005 (04. 11.2005) US AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, (71) Applicant (for all designated States except US): UNIVER¬ GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, SITY OF MISSOURI-COLUMBIA [US/US]; Office of JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, Technology & Special Projects, 475 McReynolds Hall, Co LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MY, lumbia, Missouri 6521 1-2015 (US). MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, (72) Inventors; and RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, (75) Inventors/Applicants (for US only): CALDWELL, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW Charles W. [US/US]; 475 McReynolds Hall, Columbia, (84) Designated States (unless otherwise indicated, for every Missouri 6521 1-2015 (US). SHI, Huidong [US/US]; 475 kind of regional protection available): ARIPO (BW, GH, McReynolds Hall, Columbia, Missouri 6521 1-2015 (US). GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, RAHMATPANAH, Farahnaz [US/US] ;475 McReynolds ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), [Continued on next page] (54) Title: DNA METHYLATION BIOMARKERS IN LYMPHOID AND HEMATOPOIETIC MALIGNANCIES (57) Abstract: Differential Methylatoin Hybridization (DMH) was used to identify novel methylation markers and methylation profiles for hematopoieetic malignancies, leukemia, lymphomas, etc. (e.g., non-Hodgkin's lymphomas (NHL), small B-cell lymphomas (SBCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL), chronic lymphocytic leukemia (CLL), mulitple myeloma (MM), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), etc.). Particular aspects provide novel biomarkers for NHL and subtypes thereof (e.g., MCL, B-CLL/SLL, FL, DLBCL, etc.), AML, ALL and MM, and further provide non-invasive tests (e.g. blood tests) for lymphomas and leukemias. Additional aspects provide markers for diagnosis, prognosis, monitoring responses to therapies, relapse, etc., and further provide targets and methods for therapeutic demethylating treatments. Further aspects provide cancer staging markers, and expression assays and approaches comprising idealized methylation and/or patterns" (IMP and/or IEP) and fusion of gene rankings. European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, For two-letter codes and other abbreviations, refer to the "Guid- FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, NL, PL, PT, ance Notes on Codes and Abbreviations" appearing at the begin- RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, ning of each regular issue of the PCT Gazette. GN, GQ, GW, ML, MR, NE, SN, TD, TG). Published: — without international search report and to be republished upon receipt of that report DNA METHYLATION BIOMARKERS IN LYMPHOID AND HEMATOPOIETIC MALIGNANCIES FIELD OF THE INVENTION Particular aspects are related generally to DNA methylation and cancer, and more particularly to novel compositions and methods based on novel methylation and/or expression markers having substantial utility for cancer detection, monitoring, diagnosis, prognosis, staging, treatment response prediction/monitoring, etc., where the cancers include hematopoietic malignancies, leukemia, lymphomas, etc., (e.g., non-Hodgkm's lymphomas (NHL), small B-cell lymphomas (SBCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL), chronic lymphocytic leukemia (CLL), mulitple myeloma (MM), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), etc.). CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to United States Provisional Application Serial Numbers 60/731,040, filed 27 October 2005, and 60/733,648, filed 04 November 2005, both of which are incoporated herein by reference in their entirety. STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH Aspects of this disclosure were developed with funding from NIH grant CA097880-01. The United States government has certain rights in this invention. SEQUENCE LISTING A Sequence Listing in paper form (— pages) and comprising SEQ ID NOS : 1 is attached to this application, is part of this application, and is incorporated herein by reference in its entirety. BACKGROUND CpG methylation. Methylation of cytosine residues at CpG dinucleotides is a major epigenetic modification in mammalian genomes and is known to frequently have profound effects on gene expression. This epigenetic event occurs globally in the normal genome, and 70- 80% of all CpG dinucleotides are heavily methylated in human cells. However, -0.2 to 1-kb long DNA sequence stretches of GC-rich (G+C content: >50-60%) DNA, called CpG islands (CGI), appear to be protected from the modification in somatic cells. CpG islands are frequently located in the promoters and first exon regions of 40 to 50% of all genes. The rest may be located in the intronic or other exonic regions of the genes, or in regions containing no genes. Some of these normally unmethylated promoter CGIs become methylated in cancer cells, and this may result in loss of expression of adjacent genes. As a result, critical genes may be silenced, leading to clonal proliferation of tumor cells. In cancer cells, patterns of DNA methylation are altered, and promoter (including the first exon) CpG island hypermethylation is a frequent epigenetic event in many types of cancer. This epigenetic process can result in gene silencing via alteration of local chromatin structure in the 5' end of regulatory regions, preventing normal interaction of the promoters with the transcriptional machinery. If this occurs in genes critical to growth inhibition, the silencing event could promote tumor progression. Although the list of methylation-repressed genes in Non-Hodgkin's Lymphomas (NHLs) is expanding rapidly, there is a substantial need in the art for identification of novel epigenetic biomarkers to provide for earlier and more accurate diagnoses, and for guiding therapy-related issues. Non-Hodgkin 's Lymphoma . Non-Hodgkin's Lymphoma (NHL) is the 5th most common malignancy in the United States, accounting for approximately 56,390 new cases in year 2005. Unfortunately, the incidence has increased yearly over past decades for unknown reasons, and is one of only two cancers increasing in incidence. Mature B-cell NHL including mantle cell lymphoma (MCL), B-cell chronic lymphocytic lymphoma/small lymphocytic lymphoma (B- CLL/SLL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL) comprise >80 % of all NHL cases. Together, B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL), mantle cell lymphoma (MCL), and grades I and II follicular lymphoma (FLI/FLII) comprise one-third of all NHL cases [I]. The NHLs B-CLL/SLL and FLI/FLII are generally thought to be of low aggressiveness, but still exhibit a spectrum of clinical behavior. B-CLL/SLL is a lymphoma of at least 2 subtypes comprising both pre- germinal center and post-germinal center derivation, while MCL is also of pre-germinal center derivation, and FLI/FLII derives from germinal centers of lymphoid tissues. B-CLL/SLL is diverse across different groups of patients. Many B-CLL/SLL and FLI/FLII patients have a relatively good prognosis, with median survival of —7-10 years, but usually are not curable in advanced clinical stages. MCL is a pre-germinal center derived malignancy, and FLs are germinal center derived NHLs. MCL is typically more rapidly progressive than these other SBCLs. Although advances in cancer treatment over the past several decades have improved outcomes for many patients with NHLs, the diseases are still not generally curable. The time from diagnosis to death is variable, ranging from months to many years. Current classification systems are based on clinical staging, chromosomal abnormalities and cell surface antigens, and offer important diagnostic information. Diagnostically, it is usually possible to discern each type of SBCL from the other on the basis of histologic pattern, but, there is still considerable overlap in biology, clinical behavior/disease and genetic and epigenetic alterations among the SBCL subtypes. Indolent SBCL subtypes are B cell malignancies that correlate with different stages of normal B cell differentiation. Biologically, a naive B-cell that has not been stimulated with antigen expresses a different set of genes from antigen-stimulated B-cells. There is, therefore, a substantial need in the art for novel compositions and methods for distinguishing subtypes, and, to provide improvements in therapy, as well as better ways to detect NHL and to monitor responses to therapy. Multiple Myeloma. A number of individual genes have been reported silenced in multiple myeloma MMs.
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