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Aging and Hematopoiesis

AA&MDSIF Scientific SymposiumMarch 18, 2016

Christopher Y. Park, MD, PhDHuman Oncology and Pathogenesis ProgramDepartments of Pathology/Laboratory MedicineMemorial Sloan Kettering Cancer CenterNew York, NY USA

Disclosures

Nothing to disclose

MDS is an Age-Associated Disease

MDS incidence in different age groups in the United States (2001 to 2008). (Adapted from NCI SEER*Stat Database.)

PresenterPresentation NotesIncidence rate of myelodysplastic syndromes (MDS) in different age groups in the United States (2001 to 2008). (Adapted from NCI SEER*Stat Database.8)

Stem Cell Theory of Aging

Liu and Rando 2011 JCB vol. 193 no. 2 257-266

Hematopoiesis Changes with Age

Gazit et al. 2008 Seminars in Hematology

Aging

Increased HSC number Decreased HSC long-termreconstitution potential

Myeloid Biased Differentiation

Decreased lymphocyte function/production

Decreased red cells Clonal Expansion Risk of MDS/AML

Harrison DE, et alk, J Immunol, 1989.Van Zant G, et al., JEM, 1990.Morrison SJ, et al. Nat. Med, 1996.De Haan GNW, et al., Blood, 2007.Sudo K, JEM, 2000.Muller-Sieberg CE, Blood, 2002.Muller-Sieberg CE, Blood, 2004.Rossi DJ, et al, PNAS, 2005. Rossi DJ, et al, Nature, 2007.Chambers SM, et al, Plos Biol, 2007.Cho RH, et a., Blood 2008.Pang WW, et al, PNAS, 2011.Dykstra B, et al. JEM, 2011.Farrell TL, et al., Exp Hematol, 2014And many, many more

PresenterPresentation NotesWhat is known about aging of hematopoietic system? Hematopoietic aging extensively studies in mouse models. Collectively these data show that aging results a relative decrease in lymphoid output whereas myeloid potential maintained or increased.

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HSC (LSK CD150+34-)

9-11wk 12m 27m

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G1

S-G2M

Age-Related HSPC Changes Occur Gradually

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Fold

Cha

nge

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HSC (LSK CD150+34-)

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9-11wk 12m 27m

Safak Yalcin

PresenterPresentation NotesAged HSC Compartment is Expanded

Age-Related Changes Occur Gradually in Human HSCs

Pang, et al., PNAS, 2013

PresenterPresentation NotesAged HSC Compartment is Expanded

Mechanisms of HSC Aging

J Oh, YD Ll, AJ Wagers, Nat Med, 2014

PresenterPresentation NotesFigure 1 Common pathways contributing to stem cell loss and dysfunction in the aging process. Common aging phenotypes within the stem cell are shown in red, in the niche in pink, and the strategies by which to target and hopefully reverse these mechanisms in purple.

Signaling Pathways Involved in Stem Cell Aging

J Oh, YD Ll, AJ Wagers, Nat Med, 2014

PresenterPresentation NotesFigure 3 Signaling pathways involved in aging of stem cells. Major signaling pathways related to aging of stem cells are listed in groups according to stem cell functions that they regulate.

Summary (1)

The aging hematopoietic system undergoes many changes. Many of the changes observed in the hematopoietic system

with age are due to alterations in HSCs and committed progenitors.

Age-related hematopoietic changes occur gradually over time, but can potentially be reversed.

HSC

MPP LMPP

Lin-CD34+CD38-

Adapted from Bryder et al, 2006 Am J Path; Majeti, Park, et al, Cell Stem Cell 2007

The MDS Disease-Initiating Cell is the HSC

MDS cell of origin: HSCNilsson et al., Blood, 2000Nilsson et al., Blood, 2002Tehranchi et al. NEJM 2010Will et al., Blood 2012Pang et al., PNAS, 2013Meydouf et al, Cell Stem Cell, 2014Woll et al., Cancer Cell, 2014

Pang et al., PNAS 2011

Similarities Between MDS HSCs and Old HSCs

Age MDSIncreased HSC number Decreased HSC long-termreconstitution potential

Myeloid Differentiation Bias Decreased lymphoid production

Decreased red cellproduction

Clonal Expansion Risk of MDS/AML

Clonal Hematopoiesis in Aging

Xie et al, Nat Med, 2014

Jaiswal, et al., NEJM, 2014

Clonal Hematopoieis of Indetermine Potential (CHIP) Precursor State for Myeloid Malignancies

Steensma et al. Blood 2015;126:9-16

Summary (2)

The HSC is the disease-initiating cell in MDS MDS and hematopoiesis in the elderly exhibit similar features. Clonal hematopoiesis in normal elderly characterized by the

acquisition of mutations thought to be drivers of MDS pathogenesis; however, not all aging is associated with somatic mutations.

Clonal hematopoiesis is a risk factor for MDS/AML as well as increased risk of mortality from non-hematopoietic causes.

Question: Are aged HSCs and MDS HSCs the same?

Normal HSCMDS HSC

Numerous Transcripts are Dysregulated in MDS HSCsCompared to Age-Matched Control HSCs

McGowan et al., Blood 2011 miRNAs

Steve Chung/Wenhuo Hu

Ribosomal Protein Transcript Deficiencies Characterize MDS HSC

McGowan et al., Blood 2011

Sridhar K et al. Blood 2009;114:4847-4858

HSC

CD34+

21 Rps

38 Rps

Transcriptome/DNA Methylation Differences b/w MDS and Old HSCs

Will et al., Blood, 2012

MDS HSCs are Genetically Heterogeneous

Papaemmanuil E et al., Blood, 2013Pang et al, PNAS 2013

Sorted MDS HSCs

MDS HSC Xenografts

Tehranchi R et al. NEJM 2010;363:1025-1037

scRNA-seq Reveals that MDS and Aged HSCs are Different, But Heterogeneous

union of genes in top 10% of loadings on PC2, PC3, PC4

Despite Vast Intratumoral Heterogeneity, Cells Cluster With Other Cells From the Same Patient

Single Cell RNA-seq of HSCs from Six MDS Patients (Pre- and No Treatment Samples)

Pre-Therapy MDS HSC Transcriptomes May Predict Decitabine Responses

Responders and Non-responders are Separated by PC3

Priya Vijay/Chris Mason

HSCs From Responders (R) Are More Similar to Normal HSCs than HSCs from Non-responders or Untreated Cases (PC2)

Summary (3)

MDS HSCs are distinct from aged HSCs Unique gene expression profile Unique methylome Unique protein surfaceome

MDS HSCs exhibit heterogeneity Genetic heterogeneity Transcriptional heterogeneity

MDS HSCs exhibit gene signatures May predict responses to hypomethylating agents Reflect a global reduction in ribosomal protein mRNA

MDS HSC

Dissecting the Contribution of Age to MDS Pathogenesis

YOUNG HSC

Questions: - How will we define aging? Can we develop a molecular definition of aging?

Telomere length, epigenetic changes, etc.?- Can we delineate the contribution of aging to MDS?

OLD HSC

Summary (4)

Constitutive MDS Model (work in progress) No differences in hematopoietic output when MDS BM cells

transplanted into normal recipient (young vs. old recipient?) Age-related cell-extrinsic factors modify disease phenotype

(induced) Induced MDS Model (work in progress)

Age is an independent modifier of MDS severity/progression

Rejuvenation Therapy for MDS?

Finkel et al., Nature 2007

MDS

HSC Rejuvenation?- mTOR inhibition/Rapamycin

(Chen et al., Science, 2009)- Cdc42 Inhibition/casin (Florian

et al., Cell Stem Cell, 2011)- Reprogramming/iPSC

(Wahlestedt et al, Blood, 2013)- Fasting (Cheng et al., Cell Stem

Cell, 2014)Others

PresenterPresentation NotesWhy do we want to study aging? The majority of cancer cases occur in people over 50. this true not only for leukemia as well as solid tumors such as breast, colon and prostate cancers. Here is the simplified model that views ageing and cancer from the perspective of alterations within the stem and progenitor cell pool. During normal aging , long-lived cells (such as stem cells) accumulate DNA damage The default pathway for such damaged stem cells is to undergo growth arrest, apoptosis or senescence. This decrease predisposes the organism to impaired tissue homeostasis and regenerative capacity and could contribute to ageing and age-related pathologies. Presumably, some rare cellscan escape from this normal default pathway by acquiring additional mutations that allow them to continue to proliferate even in the setting ofdamaged DNA. These proliferating but damaged cells might provide the seeds for future malignancies.Since my lab working on age-associated clonal hematopoietic diseases including aml and mds. we thought it is important to understand the steady steate aging effect on hsc function and lienage commitment.

Acknowledgements

Park LabStephen ChungWenhuo HuSarah QamarWill EngMontreh TavakkoliBenjamin DurhamGaelle MartinAlec StranahanCarolien WoolthiusChristina SpevakMona KhalajPriya SelvarajDanny Lee

Funding Sources:

Weill-CornellChris MasonPriya Vijay

MSKCCVirginia KlimekOmar Abdel-WahabSean Devlin

Aging and HematopoiesisDisclosuresMDS is an Age-Associated DiseaseStem Cell Theory of AgingSlide Number 5Slide Number 6Slide Number 7Mechanisms of HSC AgingSignaling Pathways Involved in Stem Cell AgingSummary (1)Slide Number 11Similarities Between MDS HSCs and Old HSCsClonal Hematopoiesis in AgingClonal Hematopoieis of Indetermine Potential (CHIP) Precursor State for Myeloid MalignanciesSummary (2)Numerous Transcripts are Dysregulated in MDS HSCsCompared to Age-Matched Control HSCsRibosomal Protein Transcript Deficiencies Characterize MDS HSCTranscriptome/DNA Methylation Differences b/w MD

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