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Developmental biology - Stem Cells|
Targeting Pre-leukemia Stem Cells
"Current treatments for MDS are not designed to specifically target the malignant stem cells. This makes treatment much like mowing over weeds without killing the root. Patients can achieve some benefit from chemotherapy, but eventually the MDS stem cells drive progression of the disease."
MDS begins with a protein called CD123. Previous work has shown that AML stem cells tend to be coated with CD123. The study's lead investigator and first author Brett Stevens PhD, proposed CD123 might also be detectable in patients with MDS, and therefore act as way to distinguish MDS stem cells from normal stem cells. In a series of laboratory studies, Stevens also identified unique properties in CD123 stem cells.
Genes rarely function alone, but instead are members of "pathways" that have larger functions. To zoom out from gene level to pathway level, Stevens, Jordan and colleagues used a technique called 'gene set enrichment analysis' to cluster CD123+ cells by their functions. "This let us explore not just what is turned on and off, but what these adjustments do, functionally, for the cell," Stevens says.
The major pathway magnified by CD123+ cells is one driving ribosomes. Ribosomes make proteins, and the genetic changes in CD123+ coated stem cells has ribosomes making far more proteins than they should. Interestingly, these pre-leukemia stem cells make many more proteins without making many more cells. This is important as chemotherapy targets rapidly-dividing cells. As CD123+ pre-leukemia stem cells do not divide rapidly, they resist chemotherapy.
Another significantly magnified pathway in CD123+ cells has to do with energy. In cells, mitochondria use a process called oxidative phosphorylation to make ATP - the major unit in cell energy. The more oxidative phosphorylation, the more ATP. And in CD123+ stem cells, there is much more oxidative phosphorylation.
However, the most important discovery about CD123+ cells - which do not react directly to drugs - is that the pathways they create with increased protein production and oxidative phosphorylation do respond to drugs.
Omacetaxine mepesuccinate is a protein synthesis inhibitor and FDA approved drug for treatment of chronic myeloid leukemia. When researchers treated CD123+ stem cells with omacetaxine, the drug blocked protein production and those cells died. "It looks like omacetaxine stops the protein synthesis that CD123+ stem cells need to live," Jordan explains.
Secondly, the group targeted oxidative phosphorylation, the process CD123+ stem cells use to boost ATP production. As with protein synthesis, drugs exist to block oxidative phosphorylation. One, venetoclax, blocks oxidative phosphorylation killing most patient samples of CD123+ stem cells.
Adding omacetaxine (which blocks protein synthesis) to venetoclax (which blocks oxidative phosphorylation), was highly effective against CD123+ leukemia stem cells. And only pre-leukemic stem cells are killed. Both drugs are already FDA-approved for use in human patients, raising the possibility of immediate use.
"We see not only that this combination works, but understand why it works. We hope that omacetaxine and venetoclax will be a potent combination against advanced MDS."
Increasing brown adipose tissue (BAT) thermogenesis in mice and humans improves metabolic health and understanding BAT function is of interest for novel approaches to counteract obesity. The role of long noncoding RNAs (lncRNAs) in these processes remains elusive. We observed maternally expressed, imprinted lncRNA H19 increased upon cold-activation and decreased in obesity in BAT. Inverse correlations of H19 with BMI were also observed in humans. H19 overexpression promoted, while silencing of H19 impaired adipogenesis, oxidative metabolism and mitochondrial respiration in brown but not white adipocytes. In vivo, H19 overexpression protected against DIO, improved insulin sensitivity and mitochondrial biogenesis, whereas fat H19 loss sensitized towards HFD weight gains. Strikingly, paternally expressed genes (PEG) were largely absent from BAT and we demonstrated that H19 recruits PEG-inactivating H19-MBD1 complexes and acts as BAT-selective PEG gatekeeper. This has implications for our understanding how monoallelic gene expression affects metabolism in rodents and, potentially, humans.
Elena Schmidt, Ines Dhaouadi, Isabella Gaziano, Matteo Oliverio, Paul Klemm, Motoharu Awazawa, Gerfried Mitterer, Eduardo Fernandez-Rebollo, Marta Pradas-Juni, Wolfgang Wagner, Philipp Hammerschmidt, Rute Loureiro, Christoph Kiefer, Nils R. Hansmeier, Sajjad Khani, Matteo Bergami, Markus Heine, Evgenia Ntini, Peter Frommolt, Peter Zentis, Ulf Andersson Ørom, Jörg Heeren, Matthias Blüher, Martin Bilban and Jan-Wilhelm Kornfeld.
Jan-Wilhelm Kornfeld's research is supported by the Danish Diabetes Academy, founded by the Novo Nordisk Foundation.
We thank Christiane Schäfer and Pia Scholl for HE stainings and Beatrix Martiny for electron microscopy and Julia Husa and Markus Jeitler for help with cell culture and RNA-Seq. We acknowledge Jens Alber for technical assistance. Jenny Blommer determined TG and total cholesterole levels. Linheng Li from the Stowers Institute provided H19-DMRflDMR/flDMR mice. We thank Christian Frese, Brigitte Kisters-Woike, and Corinna Klein from CECAD Proteomics Core Facility. J.W.K., E.S., I.G., N.H., S.K., and M.O. are supported by the Emmy-Noether Program of the Deutsche Forschungsgemeinschaft (DFG; KO4728/1.1). J-W.K. receives funding from University of Southern Denmark (SDU) and Danish Diabetes Academy (DDA), which is funded by Novo Nordisk Fonden (NNF). M.P.J is grateful for support by CECAD. R.L., E.F-R., M.P.J., and P.K. receive support from the European Research Council (ERC) Starting Grant TransGenRNA (No. 675014). E.S. is supported by Evangelisches Studienwerk Villigst. S.K appreciates support from DAAD. N.R.H. received a stipend from the Cologne Graduate School for Ageing (CGA). E.N. was supported by an Alexander-von-Humboldt postdoctoral fellowship. This work was supported by the DFG, Obesity Mechanisms (SFB 1052, B01) to M.B.
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Hematopoietic stem cells if mutated in specific ways, can create a type of pre-leukemic condition
known as myelodysplastic syndrome, or MDS. Image: Celgene.com