Special Emphasis Pathway in Cancer Special Emphasis Pathway in Cancer Biology Biology Paroxysmal Nocturnal Hemoglobinuria Paroxysmal Nocturnal Hemoglobinuria (PNH) (PNH) Monica Bessler, MD, PhD Washington University School of Medicine St. Louis Division of Hematology Email [email protected]Web: http://bmf.im.wustl.edu
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Special Emphasis Pathway in Cancer Biology Paroxysmal Nocturnal Hemoglobinuria (PNH) Monica Bessler, MD, PhD Washington University School of Medicine St.
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Special Emphasis Pathway in Cancer BiologySpecial Emphasis Pathway in Cancer Biology
Possible Interrelationship Between PNH, Possible Interrelationship Between PNH, Aplastic Anemia, Myelodysplastic Syndrome,Aplastic Anemia, Myelodysplastic Syndrome,
and Acute Myeloid Leukemiaand Acute Myeloid Leukemia
PIGA(-) CellsNormal Cells
Normal MarrowNormal Marrow
Model for the Development of PNH Model for the Development of PNH
MutationPIGA(-) Cells + Second Hit MutationBM Injury
Figure 3. Effects of the chromosome 12 abnormalities in 2 patients with PNH
Regulation of Ink4a/Arf during Aging
Tzatsos &Bardeesy Cell Stem Cell 2008
HMGA2 (a second factor for expansion of a PNH clone?)
• Expression of high mobility group AT-hook 2 (HMGA2), which is regulated by let-7 miRNAs (Mayr C et al, Science, 2007), contributes to proliferation of cells.
• Chromosomal abnormalities involving in HMGA2, which remove let-7-complementary sites in 3’-untranslated region (UTR), have been reported in patients with PNH (Inoue N et al., Blood, 2006) and related disorders including myeloproliferative disorders (Guglielmelli P et al., Stem Cells, 2007) and AML with myelodysplasia (Odero MD et al., Leukemia, 2005).
Mouse HMGA2
cDNABC052158
Complementary sites of let-7a
1 3 4 52 6 7
Introduction of truncated cDNA clone of Hmga2 into pPGKPuro
( )
5’-UTR 3’-UTRcoding
XhoI ClaI
Coding5’-UTR PGK-PAPGK-PROM
Specific primer pair
SalISalI
XhoI
ClaI
SalI
SalI
Replace puro with the truncated cDNA of Hmga2
Cleaved recombinant with SalI for injection
Homologous recombination for conditional truncation of Hmga2 3’-UTR
Breed truncated Hmga2+ mice with Piga- mice to see effect of Hmga2 on growth advantage of PNH
hematopoietic cells
• Time courses of changes in proportion of GPI- cells• Blood cell count• Competitive repopulation assay• Spontaneous or ENU-induced leukemogenesis
2 mice 1 mouse(need more breeding)
AcknowledgementsAcknowledgementsWashington University St. Louis:Kazu IkedaJeffrey HickenMarek JasinskyPeter Keller Bing Han Ike PantazopoulosShashikant KulkarniPhilip J. Mason Division of HematologyMorey BlinderJoshua Fields
Bone Marrow Transplant TeamJohn DiPersioPeter Westervelt
Hereditary Cancer CoreChissie KampJennifer Ivanovich
Division of RheumatologyCelia Fang John Atkinson
Dept. PathologyRichard BurackSusan Treese
Center for Clinical StudiesParticipating Medical CentersForTRIUMPHSEPHEREDEMBRACE