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Novel Approach for Epigenetic Dysregulation in Cancer

Back to Normal:. Novel Approach for Epigenetic Dysregulation in Cancer. Kyoto University BMC Team 2008. War on cancer broke out …. Eradication of cancer. More specific target on the molecular basis. Cancer was act of the God. has not been achieved. Cancer = “the disease of genes”.

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Novel Approach for Epigenetic Dysregulation in Cancer

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  1. Back to Normal: Novel Approach forEpigenetic Dysregulation in Cancer Kyoto University BMC Team 2008

  2. War on cancer broke out … Eradication of cancer More specific target on the molecular basis Cancer was act of the God has not been achieved...

  3. Cancer = “the disease of genes” Novel mechanism to regulate patterns of gene expression Epigenetics

  4. Epigenetics What regulates epigenetic change? Changes in gene expression that are not accompanied by changes in DNA sequence Chromatin remodeling

  5. Protein factor Protein factor Chromatin structures Heterochromatin Euchromatin Chromatin remodeling Gene expression Gene expression Activated Repressed

  6. Me Me Me Ac Ac Ac Chromatin remodeling Change in the pattern of gene expression Histone modification DNA methylation CpG CpG Me Me Histone Methylation Histone Acetylation Methylation at CpG site

  7. Ac Ac Ac Epigenetic changes are reversible Enzymes for epigenetic modification DNA methyltransferase DNA demethylase Histone demethylase Histone methyltransferase Histone acetyltransferase Histone deacetylase Histone acetyltransferase Histone deacetylase

  8. Cancer tissue New pathway in tumorigenesis Epigenetic dysregulation Normal cells Cancer stem cell Gene expression: Regulated Gene expression: Dysregulated Gene expression: Dysregulated Attractive target for cancer eradication

  9. Epigenetic Dysregulation in Cancer 1st Epigenetics By Takayuki Miyamoto 2ndEpigenetic Dysregulation in Cancer Stem Cell (A) Introduction By Yuta Senzai (B) LSC in AML with MLL Abnormalities By Yuki Hattori (C) Epigenetic Dysregulation in LSC By Tomohiro Kozuki 3rd Epigenetic Therapy and future prospect By Miho Tanaka 4th Summary By Tatsunori Minamide

  10. Epigenetic Dysregulation in Cancer 1st Epigenetics By Takayuki Miyamoto 2ndEpigenetic Dysregulation in Cancer Stem Cell (A) Introduction By Yuta Senzai (B) LSC in AML with MLL Abnormalities By Yuki Hattori (C) Epigenetic Dysregulation in LSC By Tomohiro Kozuki 3rd Epigenetic Therapy and future prospect By Miho Tanaka 4th Summary By Tatsunori Minamide

  11. Patients are always at the risk of relapse…. Cancer stem cells

  12. Concepts of cancer stem cell Comprise small population Characteristics Self-renewal Cancer stem cells Aberrant differentiation Experimentally proven in many cancers leukemia, colon cancer, breast cancer brain tumor, prostate cancer etc.

  13. Cancer stem cells are the cause of relapse Cancer stem cells Cancer stem cells Targeting cancer stem cells is important Relapse Eradication Therapy not targeting cancer stem cells Therapy targeting cancer stem cells

  14. Generation of cancer stem cells Stem cells Cancer stem cells Abnormal patterns of gene expression Progenitor cells Differentiated cells

  15. Abnormal patterns of gene expression Normal cell Cancer stem cell Tumor promoting genes Normal Elevated Tumor suppressor genes Normal Repressed Regulated Dysregulated

  16. Epigenetic dysregulation Dysregulated Regulated Tumor promoting genes Tumor suppressor genes Tumor promoting / suppressor genes Normal cell Cancer stem cell

  17. From epigenetic dysregulation to tumorigenesis Epigenetic dysregulation Normal cells Cancer stem cells Cancer tissue Gene expression: Regulated Gene expression: Dysregulated Gene expression: Dysregulated Epigenetic normalization

  18. Normalize cancer stem cells Epigenetic normalization Stem cells Cancer stem cells Progenitor cells Differentiation Apoptosis Differentiated cells

  19. Epigenetic dysregulation in cancer generation Detailed mechanism has been revealed in Epigenetic dysregulation Normal cells Cancer stem cells Cancer tissue Acute Myeloid Leukemia (AML) Gene expression: Regulated Gene expression: Dysregulated Gene expression: Dysregulated Epigenetic normalization

  20. Epigenetic Dysregulation in Cancer 1st Epigenetics By Takayuki Miyamoto 2ndEpigenetic Dysregulation in Cancer Stem Cell (A) Introduction By Yuta Senzai (B) LSC in AML with MLL Abnormalities By Yuki Hattori (C) Epigenetic Dysregulation in LSC By Tomohiro Kozuki 3rd Epigenetic Therapy and future prospect By Miho Tanaka 4th Summary By Tatsunori Minamide

  21. AML with MLL abnormalities • Characteristics 2. Various Symptoms 3. Treatments & Prognosis

  22. Characteristics 5～10% of AML ・ Infant leukemia ・ Therapy-related leukemia Abnormalities in MLL gene MLL gene ・ One of the transcription factors Chr 11q23 ・ Translocation frequently occurs Chromosome 11 - produces fusion proteins Translocation of MLL gene

  23. AML with MLL abnormalities • Characteristics 2. Various Symptoms 3. Treatments & Prognosis

  24. Symptoms of AML Increasing Fatigue Anemia Repeated Infections & Leukopenia Excess Bleeding Thrombocytopenia

  25. AML with MLL abnormalities • Characteristics 2. Various Symptoms 3. Treatments & Prognosis

  26. Treatments & Prognosis Relapses frequently occur ・ Chemotherapy ・ Stem cell transplantation Leukemic Stem Cells (LSCs) 100 MLL abnormalities Intermediate 75 AML with MLL abnormalities has poor prognosis P < 0.001 Population surviving 50 25 ※ Intermediate group : Neither favorable nor adverse group 0 1 2 3 4 5 6 7 Years from diagnosis Schoch C., et al. Blood. 102, 2395-2402 (2003)

  27. Hematopoietic stem cells (HSCs) Self-renewal Progenitor cells Differentiation Erythrocyte Megakaryocyte/ platelets Macrophage Granulocyte Dendritic cell NK-cell T-cell B-cell

  28. Hematopoietic stem cells (HSCs) Leukemic stem cells (LSCs) Progenitor cells How does MLL fusion gene induce leukemic transformation ? Proliferation Apoptosis Differentiation Block Erythrocyte Megakaryocyte/ platelets Macrophage Granulocyte Dendritic cell

  29. MLL fusion gene induces leukemogenesis Donor mouse HSC HSCs / LSC Progenitor cells Progenitor cells Recipient mouse MLL fusion gene Develop AML HSCs and progenitor cells transform into LSCs A.Cozzio, et al., Genes & Dev. 17, 3029-35 (2003)

  30. Analysis of gene expression patterns Dysregulated Progenitor cells HSCs LSCs HSC LSC MLL fusion gene Which gene is a key regulator? Progenitor cells Many tumor-related genes show abnormal patterns Gene expression profile A.V.Krivtsov., et al.Nature. 442, 818-22 (2006)

  31. HSC Progenitor cells LSC 4 3.5 3 2.5 Relative expression (fold) 2 1.5 1 0.5 0 Hoxa9 Hoxa10 Expression pattern of Hox gene Homeobox (Hox) gene Transcription factor for many tumor-related genes MLL fusion gene induces elevated Hox gene expression Hematopoiesis & Leukemic transformation Highly expressed in LSCs with MLL fusion gene T.C.P.Somervaille & M.L.Cleary Cancer Cell10 257–68 (2006)

  32. From MLL fusion gene to leukemogenesis Normal cellular state AML with MLL abnormalities MLL fusion gene Hoxgene Hoxgene Many tumor-related genes Many tumor-related genes Dysregulated Regulated Normal hematopoiesis Generation of LSCs

  33. Epigenetic Dysregulation in Cancer 1st Epigenetics By Takayuki Miyamoto 2ndEpigenetic Dysregulation in Cancer Stem Cell (A) Introduction By Yuta Senzai (B) LSC in AML with MLL Abnormalities By Yuki Hattori (C) Epigenetic Dysregulation in LSC By Tomohiro Kozuki 3rd Epigenetic Therapy and future prospect By Miho Tanaka 4th Summary By Tatsunori Minamide

  34. From MLL fusion gene to leukemogenesis Normal cellular state AML with MLL abnormalities What regulates Hox gene expression? MLL fusion gene Histone methylation patterns Hoxgene Hoxgene Many tumor-related genes Many tumor-related genes Dysregulated Regulated Normal hematopoiesis Generation of LSC

  35. HMT HMT Histone methylation pattern Histone methyltransferase (HMT) - methylate lysine residue - regulate gene expression H4 K Gene expression H2A H3 Methylation H2B K Core histone K : Lysine residue Different methylation pattern leads to a different expression

  36. Analyses of histone methylation patterns Chip What kinds of HMTs methylate H3K4 and H3K79? HSC MLL fusion gene LSC H3K79 methylation H3K4 methylation Progenitor cells Input (2%) αHA K79 H3K4 ＋ H3K79 － H3K4 － H3K79 ＋ H3 H3 MLL and Dot1 K4 Hox gene Hox gene Regulated Dysregulated Okada Y., et al.Cell. 121, 167-78 (2005)

  37. DOT1 Two HMTs : MLL and DOT1 H3K4 methylation in normal cell H3K79 methylation in LSC MLL DOT1 MLL K4 K4 K79 K79 MLL fusion Regulated Dysregulated Normal expression Elevated expression K79 H3 H3 K4 Hox gene Hox gene Dou Y. & Hess J.L.Int J Hematol.87, 10-18 (2008)

  38. From MLL fusion gene to leukemogenesis MLL DOT1 MLL fusion MLL fusion H3K4 methylation H3K79 methylation Can we control leukemogenesis by inhibiting Dot1 activity ? Hoxgene Hoxgene Many tumor-related genes Many tumor-related genes Dysregulated Regulated Normal cellular state Generation of LSC

  39. 100 80 60 Colony formation 40 20 0 0 Control siRNA Knockdown of DOT1 function by siRNA siRNA LSC siRNA Transduction of siRNA prevents self-renewal capacity of LSCs DOT1 K79 K79 ※ siRNA : inhibits translation of Dot1 MLL fusion Okada Y., et al.Cell. 121, 167-78 (2005)

  40. MLL DOT1 MLL fusion MLL fusion H3K4 methylation H3K79 methylation Hoxgene Hoxgene Many tumor-related genes Many tumor-related genes Dysregulated Regulated Normal cellular state Generation of LSC DOT1 is an important therapeutic target Okada Y., et al.Cell. 121, 167-78 (2005)

  41. Epigenetic dysregulation in cancer generation Epigenetic dysregulation (e.g. Dot1) Normal cells Cancer stem cell Cancer tissue Gene expression: Regulated Gene expression: Dysregulated Gene expression: Dysregulated (e.g. Dot1 inhibitor - not in clinical field) Epigenetic normalization

  42. Epigenetic Dysregulation in Cancer 1st Epigenetics By Takayuki Miyamoto 2ndEpigenetic Dysregulation in Cancer Stem Cell (A) Introduction By Yuta Senzai (B) LSC in AML with MLL Abnormalities By Yuki Hattori (C) Epigenetic Dysregulation in LSC By Tomohiro Kozuki 3rd Epigenetic Therapy and future prospect By Miho Tanaka 4th Summary By Tatsunori Minamide

  43. Epigenetic dysregulation in cancer generation Epigenetic dysregulation Normal cells Cancer stem cells Cancer tissue Gene expression: Regulated Gene expression: Dysregulated Gene expression: Dysregulated Epigenetic normalization

  44. Enzyme Enzyme Enzyme Enzyme Enzyme Enzyme Normal cell Cancer stem cell Tumor Promoting genes Tumor Suppressor genes Tumor Promoting / Suppressor genes Modifies epigenetic dysregulation Epigenetic therapy Enzyme Inhibits enzyme Dysregulated Regulated Go back to normal

  45. Epigenetic regulators and cancer types Miremadi A, et al. Hum Mol Genet.16:R28-49 (2007)

  46. Myelodysplastic syndrome (MDS) Expression of tumor suppressor genes Hypomethylation Hypermethylation Me Me Me Me Me Me Normal Repressed A hematological malignancy with pancytopenia 100 Hypermethylation Hypomethylation 80 P=0.002 60 % Alive 40 20 0 10 15 20 0 5 Years Normalizing hypermethylation has clinical significance Aggerholm A, et al. Eur J Haematol 7623–32 (2006)

  47. 1.0 0.9 0.8 0.7 0.6 ＊ ＊ 0.5 Proportion Surviving 0.4 0.3 0.2 0.1 0 0 5 10 15 20 25 30 35 40 Months Treatment of MDS with DNMT inhibitor Expression of Tumor suppressor genes Azacitizine Supportive care Normal Repressed P=0.0001 Me Me Me Me Me DNMT DNMT Azacitidine Therapy targeting hypermethylation results in better prognosis ※ DNMT : DNA methyltransferase P.Fenaux et. al., Blood.110:250a (2007)

  48. Advantages of epigenetic therapy • Not inducing genetic damage • Normalizing expression patterns of many tumor-related genes Epigenetic therapy aims at broad targets • No severe side effects One problem still remains…

  49. Our hypothesis on current epigenetic therapy Whole cancer tissue Cancer Stem cells Cancer tissue Some epigenetic regulators might be overlooked Cancer stem cells remain Schematic gene profile image of epigenetic regulators Target epigenetic regulatorsin whole cancer tissue

  50. Cancer stem cell is a cause of relapse Cancer stem cells Cancer stem cells Relapse Eradication Therapy not targeting cancer stem cells Therapy targeting cancer stem cells

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