Irving Weissman (Stanford University School of Medicine, USA)
“Normal and Neoplastic Stem Cells”
- Marrow or MPB (mobilized peripheral blood)
- Mixture of cells: HSCs, T cells, cancer cells
- Deplete mature blood cells by labeling with magnetic antibodies
- Pure HSCs for transplantation
- 250,000 fold depletion an ever cells or T cells
- Unwanted cells : cancer cells, T cells
- Noise HSC: ckit_sca1+150+34-flk2-48-Lin-
- Human HSC: CD34+90+38loLin-45RA-
- The problem (rescue blood system with un-purified graft giving cancer back)
- The solution (rescue with purified cancer free stem cells)
- Blood stem cell only come from blood
- Estimated MBC remaining after chemo ~ 1M; in models anti-CD47 clears these
- HoxB5+LT HSC are attached to bone marrow venous sinusoid always endothelial abluminal surfactant; 100 niches in a mouse femur
- http://symposium.cshlp.org/content/81/1.long
- Blood forming cells are attached to the bone
- Leukemia cells in AML patients
- Cell of origin – progression to leukemia. [competition!)
- Three labs’ work. Sic Translation Medicine 2012 4(149):149ra18
- (Steve Quake, Ravi Majettic, Irv Weissman)
- Identification of somatic mutations by exosome sequencing
- SKP2
- TET2 (Y1649 stop). Demethylation. CTCF FLT3 leukemia
- Ryan Corces, Ravi Mejetui and IW. 2014 PNAS (21 AMLs)
- ** if you want to know which genes are likely oncogene, ask the cancer
- Lessons for leukemia and perhaps all cancers
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| The importance of Purified Cancer-Free Stem Cells! adapted from https://goo.gl/qAkPE3 |
Cancers have their own self-renewing cells called cancer stem cells (Reyna, Morrison, Clarke and Weissman 2001)
— Diehn and Clarke stem cells have higher glutathione than progeny target
CD47 is a “don’t eat me cell”
- CD47 was discovered as a marker of aging RBC by Oldenburg. We found it on many LSC. Traver and IW 1998 Jaiswal Majeti Chao and IW 2008
- Hypothesis: increased expression of CD47 on myeloid leukemia /tumor cells contributes to pathogens is by facilitating evasion of phagocytoskie
- Macrophage (SIRPa interacts with CD47)
- CD47 inhibitors programmed cell removal – PrCR
- Jaiswal et al 2009 2009 Cell 138(20:p271 (metastasis niche is formed by HSC?)
- breast cancer cell + anti-CD47. –> cure
- CD47 E5 enhance is active specifically in breast cancer (MCF7 vs Jurkat)
- Anti CD47 antibody treats human brain cancers, and all many other cancers
- Paola Betamncur
- Pre-cancer cells express calreticulin, and emergent cancer clones overcome this with CD478 (真假?)
- eat me signal (Lrp 1). <-> Calreticulin
- Macrophage are the main source of calreticulin which they secrete to test target cells for eat me markers
- Nat Commun 2018 (Marjon KD and Feng M)
- MN. PMN _Mac
- Calreticulin binds to an asial CalR
- Myelodysplastic syndromes (MDS)
- PNAS 2013: combinatory therapy of antiCD47 and antiCD20 (macrophage also have Fc)
- Other don’t eat me signals Gordon, Ring, Maute IW Nature 2017
- MHC1 beta2m on cancer cells, LILRB1 (ITAM contaminating) on macrophages
- Baykal, Maute IW 2018
- Anti-PD1 or anti-PDL1 functions, other don’t eat me signals
- PDL1 is a “don’t eat me” signal in TAMs, there are others
- Receptor mediated lymphomagenesis Weissman lab (1976-1987)
- Human NHL has anti-sled surface Is. Ataudt, Levy
- ps KSHV K7 vIAP 2005 EMBO J by Wang HW and Boshoff
Anti-CD47 antibodies enable phagocytosis of AML LSC Mark Chao Majeti et al