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The Hierarchical Organization of Normal and Malignant Hematopoiesis NORMAL Hematopoie2c Stem Cell (HSC) Leukemia Stem Cells (LSC) MPP MLP Leukemic Progenitors CMP MEP GMP B/NK ETP Leukemic Blasts Erythrocytes Monocytes Megakaryocytes/ NK B cells T Cells Granulocytes Platelets Dendri2c cells cells Human hematopoie2c stem cells iden2fied on the basis of xenotransplant repopula2on STABLE MULTILINEAGE! HEMATOPOIETIC GRAFT! Human hematopoietic! stem cells! Immune-deficient recipient! 20 yrs of assay op2miza2on -‐intrafemoral injec2on -‐T, B, NK, deficiency -‐macrophage impairment due to Nod allele of SIRP-‐α -‐female NSG recipients 10x more sensi2ve Quantitative repopulation assay permits study of human stem cell biology:! • self-renewal! • differentiation! • Proliferation! Elucida2on of the human hematopoie2c hierarchy at single cell resolu2on From: Doulatov et al Cell Stem Cell 2012 What is Cancer? • • • • Cannot differen2ate properly Uncontrolled prolifera2on Cannot die properly ….etc Individual cancer cells vary in many cancer hallmarks True, but…… Is every tumour cell equal and able to maintain long term clonal growth? Hanahan and Weinberg Cell 2011 Figure 6. Therapeutic Targeting of the Hallmarks of Cancer Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials cases approved for clinical use in treating certain forms of human cancer. Additionally, the investigational drugs are being developed to target e enabling characteristics and emerging hallmarks depicted in Figure 3, which also hold promise as cancer therapeutics. The drugs listed are but examples; there is a deep pipeline of candidate drugs with different molecular targets and modes of action in development for most of these hallma Func2onal assay for leukemia-‐ini2a2ng cells PB or BM from leukemia patient! Immune-deficient recipient! LEUKEMIC GRAFT! Leukemia Initiating Cell (L-IC)! • Rare-frequency in AML ~ 1 in 106 (varies from patient to patient)! • Dormant-able to survive common anti-proliferative chemotherapy! The Cancer Stem Cell Model • apex of neoplastic “hierarchy”! • CSCs possess 2 key stem cell properties:! • self-renewal-long term clonal maintenance! • ability to differentiate and regenerate tumour heterogeneity! • Epigenetic or developmental program in operation! • Tumors are caricatures of normal development! NO TUMOR NO TUMOR NO TUMOR NO TUMOR NO TUMOR NO TUMOR The Hierarchical Organization of Normal and Malignant Hematopoiesis NORMAL LEUKEMIC Hematopoie2c Stem Cell (HSC) MPP Leukemia Stem Cells (LSC) MLP CMP MEP GMP B/NK ETP Erythrocytes Monocytes Megakaryocytes/ NK B cells T Cells Granulocytes Platelets Dendri2c cells cells Hypothesis: If LSC are only cell type capable of Leukemic Progenitors sustaining clonal growth then their properties ultimately govern patient survival Leukemic Blasts Iden2fica2on of LSC specific gene signatures Iden2fica2on of LSC genes Sort cells HSC Progenitors Mature Patient blood sample (n=84) AML cells (LSC+) 160 unique genes differentially expressed no AML cells (LSC-) Gene expression measurement With Jean Wang and Mark Minden L1 regression analysis on training cohort n=495) adapted from Eppert (et al., Nat Med, 2011 18 gene LSC signature Overall Survival LSC signature is prognos2c in 4 independent datasets HR = 3.1637, p = 8.24e-‐08 median survival: NA (low risk), 223 (high risk) Metzeler primary GSE12417 n=156 HR = 2.6217, p = 1.5e-‐07 median survival: 1029 (low risk), 303 (high risk) Ley-‐TCAG Full GSE10358 n=183 Survival Time HR = 2.6595, p = 0.00268 median survival: NA (low risk), 301 (high risk) Metzeler Secondary GSE12417 n=70 HR = 2.0617, p = 0.00636 median survival: 723 (low risk), 314 (high risk) Ley-‐TCAG NK-‐AML GSE10358 n=83 LSC signature prognos2c across 1000 cancer genomes Low LSC signature High LSC signature Ø Stemness influences pa2ent survival Ø Many gene2c drivers must converge on stemness Ø Determinants of stemness represent a common therapeu2c target Oien considered as mutually exclusive mechanisms of tumor heterogeneity Gene2c Diversity Epigene2cs and Developmental Pathways-‐> Hierarchies Tumour Micro-‐ environment Ø Heterogeneity contributes to therapy failure and disease recurrence Mechanisms of tumor heterogeneity impinge on stemness Key Ques2ons in the genesis of AML What is the First Hit? What is the cell of origin: Stem cell or progenitor? NORMAL HEMATOPOIETIC CELL Liran Shlush Sasan Zandi CSCC Disease Team Genomics Program Tom Hudson, John McPherson LSC Team Jean Wang, Mark Minden Why will these cells progress to AML? PRELEUKEMIC CELL What is the sequence of subsequent hits? LEUKEMIC STEM CELL Shlush, Zandi et al Nature, 2014 Pre-leukemia: backtracking AML to it’s origins Ini2a2ng muta2on NORMAL Preleukemic Stem Cell (preLSC) Hematopoie2c Stem Cell (HSC) ACUTE MYELOID LEUKEMIA Addi2onal muta2ons MPP MLP Clonal expansion Mul2lineage differen2a2on Leukemia Stem Cells (LSC) CMP MEP Leukemic Progenitors GMP B/NK ETP Erythrocytes Monocytes Megakaryocytes/ NK B cells T Cells Granulocytes Platelets Dendri2c cells cells Leukemic Blasts
