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2. Retained functional normal and preleukemic HSCs at diagnosis are associated with good prognosis in DNMT3AmutNPM1mut AMLs

Author

Donato, Elisa, Correia, Nadia, Andresen, Carolin, Karpova, Darja, Würth, Roberto, Klein, Corinna, Sohn, Markus, Przybylla, Adriana, Zeisberger, Petra, Rothfelder, Kathrin, Salih, Helmut, Bonig, Halvard, Stasik, Sebastian, Röllig, Christoph, Dolnik, Anna, Bullinger, Lars, Buchholz, Frank, Thiede, Christian, Hübschmann, Daniel, and Trumpp, Andreas

Published
2023
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3. Targeting CXCR4, VLA-4, and CXCR2 for hematopoietic stem cell mobilization

Author

Cancilla, Daniel, primary, Rettig, Michael P., additional, Karpova, Darja, additional, Thakellapalli, Haresh, additional, Singh, Megh, additional, Meyers, Marvin J., additional, Ruminski, Peter G., additional, Christ, Stephanie, additional, Chendamarai, Ezhilarasi, additional, Gao, Feng, additional, Gehrs, Leah, additional, Ritchey, Julie K., additional, Prinsen, Michael, additional, and DiPersio, John F., additional

Published
2024
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6. Targeting VLA4 integrin and CXCR2 mobilizes serially repopulating hematopoietic stem cells

Author

Karpova, Darja, Rettig, Michael P., Ritchey, Julie, Cancilla, Daniel, Gehrs, Stephanie ChrisLeah, Chendamarai, Ezhilarasi, Evbuomwan, Moses O., Zhang, Matthew HolJingzhu, Abou-Ezzi, Grazia, Celik, Hamza, Wiercinska, Eliza, Yang, Wei, Gao, Feng, Eissenberg, Linda G., Heier, Richard F., Arnet, Stacy D., Meyers, Marvin J., Prinsen, Michael J., Griggs, David W., Trumpp, Andreas, Ruminski, Peter G., Morrow, Dwight M., Bonig, Halvard B., Link, Daniel C., and DiPersio, John F.

Subjects
R and D Systems, Hematopoietic stem cells, Combination drug therapy, Software industry, Hematopoietic stem cell transplantation, Integrins, Plerixafor, Stem cells, Antigens, Surgery, Stem cell transplantation, Granulocyte colony-stimulating factor, Health care industry, Washington University. School of Medicine
Abstract

Mobilized peripheral blood has become the primary source of hematopoietic stem and progenitor cells (HSPCs) for stem cell transplantation, with a 5-day course of granulocyte colony-stimulating factor (G-CSF) as the most common regimen used for HSPC mobilization. The CXCR4 inhibitor plerixafor is a more rapid mobilizer, yet not potent enough when used as a single agent, thus emphasizing the need for faster acting agents with more predictable mobilization responses and fewer side effects. We sought to improve hematopoietic stem cell transplantation by developing a new mobilization strategy in mice through combined targeting of the chemokine receptor CXCR2 and the very late antigen 4 (VLA4) integrin. Rapid and synergistic mobilization of HSPCs along with an enhanced recruitment of true HSCs was achieved when a CXCR2 agonist was coadministered in conjunction with a VLA4 inhibitor. Mechanistic studies revealed involvement of CXCR2 expressed on BM stroma in addition to stimulation of the receptor on granulocytes in the regulation of HSPC localization and egress. Given the rapid kinetics and potency of HSPC mobilization achieved by the VLA4 inhibitor and CXCR2 agonist combination in mice compared with currently approved HSPC mobilization methods, the combination represents an exciting potential strategy for clinical development in the future., Introduction In postnatal mammals, the vast majority of hematopoietic stem and progenitor cells (HSPCs) reside in the protective environment of the bone marrow (BM) (1, 2). Accordingly, only very few [...]

Published
2019
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8. PB1759: RETAINED FUNCTIONAL NORMAL AND/OR PRE-LEUKEMIC HSCS IN THE BONE MARROW ARE ASSOCIATED TO GOOD PROGNOSIS IN DNMT3AMUTNPM1MUT AML PATIENTS

Author

Donato, Elisa, primary, Correia, Nadia, additional, Andresen, Carolin, additional, Karpova, Darja, additional, Würth, Roberto, additional, Klein, Corinna, additional, Sohn, Markus, additional, Przybylla, Adriana, additional, Zeisberger, Petra, additional, Rothfelder, Kathrin, additional, Salih, Helmut, additional, Bonig, Halvard, additional, Stasik, Sebastian, additional, Röllig, Christoph, additional, Dolnik, Anna, additional, Bullinger, Lars, additional, Buchholz, Frank, additional, Thiede, Christian, additional, Hübschmann, Daniel, additional, and Trumpp, Andreas, additional

Published
2023
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9. Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells

Author

Karpova, Darja, Ritchey, Julie K., Holt, Matthew S., Abou-Ezzi, Grazia, Monlish, Darlene, Batoon, Lena, Millard, Susan, Spohn, Gabriele, Wiercinska, Eliza, Chendamarai, Ezhil, Yang, Wei, Christ, Stephanie, Gehrs, Leah, Schuettpelz, Laura G., Dembowsky, Klaus, Pettit, Allison R., Rettig, Michael P., Bonig, Halvard, and DiPersio, John F.

Published
2017
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10. Supplementary Figure 3 from Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax

Author

Waclawiczek, Alexander, primary, Leppä, Aino-Maija, primary, Renders, Simon, primary, Stumpf, Karolin, primary, Reyneri, Cecilia, primary, Betz, Barbara, primary, Janssen, Maike, primary, Shahswar, Rabia, primary, Donato, Elisa, primary, Karpova, Darja, primary, Thiel, Vera, primary, Unglaub, Julia M., primary, Grabowski, Susanna, primary, Gryzik, Stefanie, primary, Vierbaum, Lisa, primary, Schlenk, Richard F., primary, Röllig, Christoph, primary, Hundemer, Michael, primary, Pabst, Caroline, primary, Heuser, Michael, primary, Raffel, Simon, primary, Müller-Tidow, Carsten, primary, Sauer, Tim, primary, and Trumpp, Andreas, primary

Published
2023
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11. Supplementary Tables 1-7 from Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax

Author

Waclawiczek, Alexander, primary, Leppä, Aino-Maija, primary, Renders, Simon, primary, Stumpf, Karolin, primary, Reyneri, Cecilia, primary, Betz, Barbara, primary, Janssen, Maike, primary, Shahswar, Rabia, primary, Donato, Elisa, primary, Karpova, Darja, primary, Thiel, Vera, primary, Unglaub, Julia M., primary, Grabowski, Susanna, primary, Gryzik, Stefanie, primary, Vierbaum, Lisa, primary, Schlenk, Richard F., primary, Röllig, Christoph, primary, Hundemer, Michael, primary, Pabst, Caroline, primary, Heuser, Michael, primary, Raffel, Simon, primary, Müller-Tidow, Carsten, primary, Sauer, Tim, primary, and Trumpp, Andreas, primary

Published
2023
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12. Data from Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax

Author

Waclawiczek, Alexander, primary, Leppä, Aino-Maija, primary, Renders, Simon, primary, Stumpf, Karolin, primary, Reyneri, Cecilia, primary, Betz, Barbara, primary, Janssen, Maike, primary, Shahswar, Rabia, primary, Donato, Elisa, primary, Karpova, Darja, primary, Thiel, Vera, primary, Unglaub, Julia M., primary, Grabowski, Susanna, primary, Gryzik, Stefanie, primary, Vierbaum, Lisa, primary, Schlenk, Richard F., primary, Röllig, Christoph, primary, Hundemer, Michael, primary, Pabst, Caroline, primary, Heuser, Michael, primary, Raffel, Simon, primary, Müller-Tidow, Carsten, primary, Sauer, Tim, primary, and Trumpp, Andreas, primary

Published
2023
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13. Supplementary Figure 2 from Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax

Author

Waclawiczek, Alexander, primary, Leppä, Aino-Maija, primary, Renders, Simon, primary, Stumpf, Karolin, primary, Reyneri, Cecilia, primary, Betz, Barbara, primary, Janssen, Maike, primary, Shahswar, Rabia, primary, Donato, Elisa, primary, Karpova, Darja, primary, Thiel, Vera, primary, Unglaub, Julia M., primary, Grabowski, Susanna, primary, Gryzik, Stefanie, primary, Vierbaum, Lisa, primary, Schlenk, Richard F., primary, Röllig, Christoph, primary, Hundemer, Michael, primary, Pabst, Caroline, primary, Heuser, Michael, primary, Raffel, Simon, primary, Müller-Tidow, Carsten, primary, Sauer, Tim, primary, and Trumpp, Andreas, primary

Published
2023
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14. Supplementary Figure 5 from Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax

Author

Waclawiczek, Alexander, primary, Leppä, Aino-Maija, primary, Renders, Simon, primary, Stumpf, Karolin, primary, Reyneri, Cecilia, primary, Betz, Barbara, primary, Janssen, Maike, primary, Shahswar, Rabia, primary, Donato, Elisa, primary, Karpova, Darja, primary, Thiel, Vera, primary, Unglaub, Julia M., primary, Grabowski, Susanna, primary, Gryzik, Stefanie, primary, Vierbaum, Lisa, primary, Schlenk, Richard F., primary, Röllig, Christoph, primary, Hundemer, Michael, primary, Pabst, Caroline, primary, Heuser, Michael, primary, Raffel, Simon, primary, Müller-Tidow, Carsten, primary, Sauer, Tim, primary, and Trumpp, Andreas, primary

Published
2023
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15. SupplementaryFigure 6 from Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax

Author

Waclawiczek, Alexander, primary, Leppä, Aino-Maija, primary, Renders, Simon, primary, Stumpf, Karolin, primary, Reyneri, Cecilia, primary, Betz, Barbara, primary, Janssen, Maike, primary, Shahswar, Rabia, primary, Donato, Elisa, primary, Karpova, Darja, primary, Thiel, Vera, primary, Unglaub, Julia M., primary, Grabowski, Susanna, primary, Gryzik, Stefanie, primary, Vierbaum, Lisa, primary, Schlenk, Richard F., primary, Röllig, Christoph, primary, Hundemer, Michael, primary, Pabst, Caroline, primary, Heuser, Michael, primary, Raffel, Simon, primary, Müller-Tidow, Carsten, primary, Sauer, Tim, primary, and Trumpp, Andreas, primary

Published
2023
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16. Supplementary Figure 4 from Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax

Author

Waclawiczek, Alexander, primary, Leppä, Aino-Maija, primary, Renders, Simon, primary, Stumpf, Karolin, primary, Reyneri, Cecilia, primary, Betz, Barbara, primary, Janssen, Maike, primary, Shahswar, Rabia, primary, Donato, Elisa, primary, Karpova, Darja, primary, Thiel, Vera, primary, Unglaub, Julia M., primary, Grabowski, Susanna, primary, Gryzik, Stefanie, primary, Vierbaum, Lisa, primary, Schlenk, Richard F., primary, Röllig, Christoph, primary, Hundemer, Michael, primary, Pabst, Caroline, primary, Heuser, Michael, primary, Raffel, Simon, primary, Müller-Tidow, Carsten, primary, Sauer, Tim, primary, and Trumpp, Andreas, primary

Published
2023
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17. Supplementary Figure 1 from Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax

Author

Waclawiczek, Alexander, primary, Leppä, Aino-Maija, primary, Renders, Simon, primary, Stumpf, Karolin, primary, Reyneri, Cecilia, primary, Betz, Barbara, primary, Janssen, Maike, primary, Shahswar, Rabia, primary, Donato, Elisa, primary, Karpova, Darja, primary, Thiel, Vera, primary, Unglaub, Julia M., primary, Grabowski, Susanna, primary, Gryzik, Stefanie, primary, Vierbaum, Lisa, primary, Schlenk, Richard F., primary, Röllig, Christoph, primary, Hundemer, Michael, primary, Pabst, Caroline, primary, Heuser, Michael, primary, Raffel, Simon, primary, Müller-Tidow, Carsten, primary, Sauer, Tim, primary, and Trumpp, Andreas, primary

Published
2023
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18. Supplementary Figure 7 from Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax

Author

Waclawiczek, Alexander, primary, Leppä, Aino-Maija, primary, Renders, Simon, primary, Stumpf, Karolin, primary, Reyneri, Cecilia, primary, Betz, Barbara, primary, Janssen, Maike, primary, Shahswar, Rabia, primary, Donato, Elisa, primary, Karpova, Darja, primary, Thiel, Vera, primary, Unglaub, Julia M., primary, Grabowski, Susanna, primary, Gryzik, Stefanie, primary, Vierbaum, Lisa, primary, Schlenk, Richard F., primary, Röllig, Christoph, primary, Hundemer, Michael, primary, Pabst, Caroline, primary, Heuser, Michael, primary, Raffel, Simon, primary, Müller-Tidow, Carsten, primary, Sauer, Tim, primary, and Trumpp, Andreas, primary

Published
2023
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19. Combinatorial BCL-2 family expression in Acute Myeloid Leukemia Stem Cells predicts clinical response to Azacitidine/Venetoclax

Author

Waclawiczek, Alexander, primary, Leppa, Aino-Maija, additional, Renders, Simon, additional, Stumpf, Karolin, additional, Reyneri, Cecilia, additional, Betz, Barbara, additional, Janssen, Maike, additional, Shahswar, Rabia, additional, Donato, Elisa, additional, Karpova, Darja, additional, Thiel, Vera, additional, Unglaub, Julia M., additional, Grabowski, Susanna, additional, Gryzik, Stefanie, additional, Vierbaum, Lisa, additional, Schlenk, Richard F., additional, Rollig, Christoph, additional, Hundemer, Michael, additional, Pabst, Caroline, additional, Heuser, Michael, additional, Raffel, Simon, additional, Muller-Tidow, Carsten, additional, Sauer, Tim, additional, and Trumpp, Andreas, additional

Published
2023
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23. Exploring Genetic and Non-Genetic Changes Driving Tumor Evolution in CK-AML at Single-Cell Resolution

Author

Leppä, Aino-Maija, primary, Grimes, Karen, additional, Jeong, Hyobin, additional, Boch, Tobias, additional, Karpova, Darja, additional, Grünschläger, Florian, additional, Jauch, Anna, additional, Dolnik, Anna, additional, Rodriguez-Martin, Bernardo, additional, Bullinger, Lars, additional, Krämer, Alwin, additional, Sanders, Ashley D, additional, Korbel, Jan O, additional, and Trumpp, Andreas, additional

Published
2022
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24. Frequent Whole Blood Donations Select for DNMT3A variants Mediating Enhanced Response to Erythropoietin

Author

Karpova, Darja, primary, Huerga Encabo, Hector, additional, Donato, Elisa, additional, Kotova, Iuliia, additional, Calderazzo, Silvia, additional, Leppä, Aino-Maija, additional, Jasper, Panten, additional, Przybylla, Adriana, additional, Seifried, Erhard, additional, Kopp-Schneider, Annette, additional, Wong, Terrence N, additional, Bonnet, Dominique, additional, Bonig, Halvard, additional, and Trumpp, Andreas, additional

Published
2022
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25. Frequent whole blood donations select for DNMT3A variants mediating enhanced response to erythropoietin

Author

Karpova, Darja, Huerga Encabo, Hector, Donato, Elisa, Kotova, Iuliia, Calderazzo, Silvia, Leppä, Aino-Maija, Panten, Jasper, Przbylla, Adriana, Seifried, Erhard, Kopp-Schneider, Annette, Wong, Terrence Neal, Bonnet, Dominique, Bönig, Halvard-Björn, Trumpp, Andreas, Karpova, Darja, Huerga Encabo, Hector, Donato, Elisa, Kotova, Iuliia, Calderazzo, Silvia, Leppä, Aino-Maija, Panten, Jasper, Przbylla, Adriana, Seifried, Erhard, Kopp-Schneider, Annette, Wong, Terrence Neal, Bonnet, Dominique, Bönig, Halvard-Björn, and Trumpp, Andreas

Abstract

Background: Blood donation saves lives. Provided they are in good health, male volunteers can donate as often as six times per year from the age of 18 into their late sixties. The burden of blood donation is very unevenly distributed, with a small minority of altruistic individuals providing this critical resource. While the consequences of persistent iron depletion in blood donors have been studied in the context of cancer and coronary heart disease, potential effects of the erythropoietic stress from repetitive large-volume phlebotomy remain unexplored. We sought to investigate if and how repeated blood donations affect the clonal composition of the hematopoietic stem and progenitor cell (HSPC) compartment. Methods: 105 healthy, male individuals with an extensive blood donation history (median of 120 donations per donor; median age of 66 yrs.) were screened for the presence of clonal hematopoiesis (CH) using a sequencing panel covering 141 genes commonly mutated in human myeloid neoplasms. The control cohort consisted of 103 healthy, male donors with a median of 5 donations per donor and a median age of 63. Donors positive for CH were subsequently studied longitudinally. The pathogenicity of detected variants was compared using established scoring systems. Finally, to assess the functional consequences of blood-donation induced CH, selected CH mutations were introduced by CRISPR-mediated editing into HSPCs from human cord blood (CB) or bone marrow (BM). The effect of these mutations was tested under different stress stimuli using functional ex vivo long-term culture initiating cells (LTC-IC) assays. Results: Compared to the control cohort, frequent donors were significantly more likely to have mutations in genes encoding for epigenetic modifiers (44.7 vs. 22.3 %), most specifically in the two genes most commonly mutated in CH, DNMT3A and TET2 (35.2 vs. 20.3 %). However, no difference in the variant allele frequency (VAF) of detected mutations was found between the

Published
2022

28. Hematopoietic-extrinsic cues dictate circadian redistribution of mature and immature hematopoietic cells in blood and spleen

Author

Stenzinger, Miriam, Karpova, Darja, Unterrainer, Christian, Harenkamp, Sabine, Wiercinska, Eliza, Hoerster, Keven, Pfeffer, Martina, Maronde, Erik, Bönig, Halvard-Björn, Stenzinger, Miriam, Karpova, Darja, Unterrainer, Christian, Harenkamp, Sabine, Wiercinska, Eliza, Hoerster, Keven, Pfeffer, Martina, Maronde, Erik, and Bönig, Halvard-Björn

Abstract

Circadian oscillations in circulating leukocyte subsets including immature hematopoietic cells have been appreciated; the origin and nature of these alterations remain elusive. Our analysis of wild-type C57BL/6 mice under constant darkness confirmed circadian fluctuations of circulating leukocytes and clonogenic cells in blood and spleen but not bone marrow. Clock gene deficient Bmal1-/- mice lacked this regulation. Cell cycle analyses in the different hematopoietic compartments excluded circadian changes in total cell numbers, rather favoring shifting hematopoietic cell redistribution as the underlying mechanism. Transplant chimeras demonstrate that circadian rhythms within the stroma mediate the oscillations independently of hematopoietic-intrinsic cues. We provide evidence of circadian CXCL12 regulation via clock genes in vitro and were able to confirm CXCL12 oscillation in bone marrow and blood in vivo. Our studies further implicate cortisol as the conveyor of circadian input to bone marrow stroma and mediator of the circadian leukocyte oscillation. In summary, we establish hematopoietic-extrinsic cues as causal for circadian redistribution of circulating mature/immature blood cells.

Published
2019

29. Targeting CXCR4, VLA4, and CXCR2 for Hematopoietic Stem Cell Mobilization

Author

Cancilla, Daniel, primary, Thakellapalli, Haresh, additional, Meyers, Marvin J, additional, Rettig, Michael P., additional, Chendamarai, Ezhilarasi, additional, Christ, Stephanie, additional, Karpova, Darja, additional, Ruminski, Peter G, additional, Ritchey, Julie K., additional, Morrow, Dwight M., additional, Prinsen, Michael, additional, and DiPersio, John F., additional

Published
2019
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32. JARID2 Functions as a Tumor Suppressor in Myeloid Neoplasms by Repressing Self-Renewal in Hematopoietic Progenitor Cells

Author

Celik, Hamza, primary, Koh, Won Kyun, additional, Kramer, Ashley C., additional, Ostrander, Elizabeth L., additional, Mallaney, Cates, additional, Fisher, Daniel A.C., additional, Xiang, Jingyu, additional, Wilson, William C., additional, Martens, Andrew, additional, Kothari, Alok, additional, Fishberger, Gregory, additional, Tycksen, Eric, additional, Karpova, Darja, additional, Duncavage, Eric J., additional, Lee, Youngsook, additional, Oh, Stephen T., additional, and Challen, Grant A., additional

Published
2018
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34. Mobilization of hematopoietic stem cells with the novel CXCR4 antagonist POL6326 (balixafortide) in healthy volunteers-results of a dose escalation trial

Author

Karpova, Darja, Bräuninger, Susanne Barbara, Wiercinska, Eliza, Krämer, Ariane, Stock, Belinda, Graff, Jochen, Martin, Hans, Wach, Achim, Escot, Christophe, Douglas, Garry, Romagnoli, Barbara, Chevalier, Eric, Dembowski, Klaus, Hooftman, Leon, Bönig, Halvard-Björn, Karpova, Darja, Bräuninger, Susanne Barbara, Wiercinska, Eliza, Krämer, Ariane, Stock, Belinda, Graff, Jochen, Martin, Hans, Wach, Achim, Escot, Christophe, Douglas, Garry, Romagnoli, Barbara, Chevalier, Eric, Dembowski, Klaus, Hooftman, Leon, and Bönig, Halvard-Björn

Abstract

Background: Certain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. We herein report results of a Phase I dose escalation trial comparing mobilization with a peptidic CXCR4 antagonist POL6326 (balixafortide) vs. G-CSF. Methods: Healthy male volunteer donors with a documented average mobilization response to G-CSF received, following ≥6 weeks wash-out, a 1–2 h infusion of 500–2500 µg/kg of balixafortide. Safety, tolerability, pharmacokinetics and pharmacodynamics were assessed. Results: Balixafortide was well tolerated and rated favorably over G-CSF by subjects. At all doses tested balixafortide mobilized HSPC. In the dose range between 1500 and 2500 µg/kg mobilization was similar, reaching 38.2 ± 2.8 CD34 + cells/µL (mean ± SEM). Balixafortide caused mixed leukocytosis in the mid-20 K/µL range. B-lymphocytosis was more pronounced, whereas neutrophilia and monocytosis were markedly less accentuated with balixafortide compared to G-CSF. At the 24 h time point, leukocytes had largely normalized. Conclusions: Balixafortide is safe, well tolerated, and induces efficient mobilization of HSPCs in healthy male volunteers. Based on experience with current apheresis technology, the observed mobilization at doses ≥1500 µg/kg of balixafortide is predicted to yield in a single apheresis a standard dose of 4× 10E6 CD34+ cells/kg from most individuals donating for an approximately weight-matched recipient. Exploration of alternative dosing regimens may provide even higher mobilization responses. Trial Registration European Medicines Agency (EudraCT-Nr. 2011-003316-23) and clinicaltrials.gov (NCT01841476)

Published
2017

37. Mobilization of hematopoietic stem cells with the novel CXCR4 antagonist POL6326 (balixafortide) in healthy volunteers—results of a dose escalation trial

Author

Karpova, Darja, primary, Bräuninger, Susanne, additional, Wiercinska, Eliza, additional, Krämer, Ariane, additional, Stock, Belinda, additional, Graff, Jochen, additional, Martin, Hans, additional, Wach, Achim, additional, Escot, Christophe, additional, Douglas, Garry, additional, Romagnoli, Barbara, additional, Chevalier, Eric, additional, Dembowski, Klaus, additional, Hooftman, Leon, additional, and Bonig, Halvard, additional

Published
2017
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38. Combined Targeting of CXCR2 and VLA4 Results in Rapid and Synergistic Mobilization of Hematopoietic Stem and Progenitor Cells in Mice

Author

Karpova, Darja, primary, Rettig, Michael P., additional, Eissenberg, Linda, additional, Ritchey, Julie, additional, Holt, Matthew, additional, Heier, Richard, additional, Arnett, Stacy, additional, Meyers, Marvin, additional, Griggs, David W., additional, Ruminski, Peter, additional, Morrow, Dwight, additional, and DiPersio, John F, additional

Published
2016
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39. Expansion and Maintenance of Hematopoietic Stem and Progenitor Cells in Course of Long-Term Inhibition of CXCR4/CXCL12 Signaling

Author

Karpova, Darja, primary, Ritchey, Julie, additional, Holt, Matthew, additional, Monlish, Darlene, additional, Schuettpelz, Laura G., additional, Yang, Wei, additional, Levesque, Jean-Pierre, additional, Pettit, Allison Robyn, additional, Rettig, Michael P., additional, Bonig, Halvard, additional, and DiPersio, John F, additional

Published
2016
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40. Variant rs1801157 in the 3'UTR of SDF-1ß does not explain variability of healthy-donor G-CSF responsiveness

Author

Schulz, Miriam, Karpova, Darja, Spohn, Gabriele, Damert, Annette, Seifried, Erhard, Binder, Vera, Bönig, Halvard-Björn, Schulz, Miriam, Karpova, Darja, Spohn, Gabriele, Damert, Annette, Seifried, Erhard, Binder, Vera, and Bönig, Halvard-Björn

Abstract

The genetics responsible for the inter-individually variable G-CSF responsiveness remain elusive. A single nucleotide polymorphism (SNP) in the 3’UTR of CXCL12, rs1801157, was implicated in X4-tropic HiV susceptibility and later, in two small studies, in G-CSR responsiveness in patients and donors. The position of the SNP in the 3’UTR together with in-silico predictions suggested differential binding of micro-RNA941 as an underlying mechanism. In a cohort of 515 healthy stem cell donors we attempted to reproduce the correlation of the CXCL12 3’UTR SNP and mobilization responses and tested the role of miR941 in this context. The SNP was distributed with the expected frequency. Mobilization efficiency for CD34+ cells in WT, heterozygous and homozygous SNP individuals was indistinguishable, even after controlling for gender. miR941 expression in non-hematopoietic bone marrow cells was undetectable and miR941 did not interact with the 3’ UTR of CXCL12. Proposed effects of the SNP rs1801157 on G-CSF responsiveness cannot be confirmed in a larger cohort.

Published
2015

41. Potent Stem Cell Mobilization with the Novel CXCR4 Antagonist POL6326 - Results of a Phase IIa Dose Escalation Study in Comparison to G-CSF

Author

Karpova, Darja, primary, Brauninger, Susanne, additional, Wiercinska, Eliza, additional, Kraemer, Ariane, additional, Stock, Belinda, additional, Graff, Jochen, additional, Escot, Christophe, additional, Douglas, Garry, additional, Romagnoli, Barbara, additional, Chevalier, Eric, additional, Dembowsky, Klaus, additional, Hooftman, Leon, additional, and Bonig, Halvard, additional

Published
2015
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42. The novel CXCR4 antagonist POL5551 mobilizes hematopoietic stem and progenitor cells with greater efficiency than Plerixafor

Author

Karpova, Darja, Dauber, Katrin, Spohn, Gabriele, Chudziak, Doreen, Wiercinska, Eliza, Schulz, Miriam, Pettit, Allison R., Levesque, Jean-Pierre, Romagnoli, Barbara, Patel, Kalpana, Chevalier, Eric, Dembowsky, Klaus, and Bönig, Halvard-Björn

Subjects
ddc:610
Abstract

Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be orroborated in humans.

Published
2013

47. Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation

Author

Ridder, Kirsten, Keller, Sascha, Dams, Maria, Rupp, Anne-Kathleen, Schlaudraff, Jessica, Del Turco, Domenico, Starmann, Julia, Macas, Jadranka, Karpova, Darja, Devraj, Kavi, Depboylu, Candan, Landfried, Britta, Arnold, Bernd, Plate, Karl, Höglinger, Günter, Sültmann, Holger, Altevogt, Peter, Momma, Stefan, Ridder, Kirsten, Keller, Sascha, Dams, Maria, Rupp, Anne-Kathleen, Schlaudraff, Jessica, Del Turco, Domenico, Starmann, Julia, Macas, Jadranka, Karpova, Darja, Devraj, Kavi, Depboylu, Candan, Landfried, Britta, Arnold, Bernd, Plate, Karl, Höglinger, Günter, Sültmann, Holger, Altevogt, Peter, and Momma, Stefan

Abstract

Mechanisms behind how the immune system signals to the brain in response to systemic inflammation are not fully understood. Transgenic mice expressing Cre recombinase specifically in the hematopoietic lineage in a Cre reporter background display recombination and marker gene expression in Purkinje neurons. Here we show that reportergene expression in neurons is caused by intercellular transfer of functional Cre recombinase messenger RNA from immune cells into neurons in the absence of cell fusion. In vitro purified secreted extracellular vesicles (EVs) from blood cells contain Cre mRNA, which induces recombination in neurons when injected into the brain. Although Cre-mediated recombination events in the brain occur very rarely in healthy animals, their number increases considerably in different injury models, particularly under inflammatory conditions, and extend beyond Purkinje neurons to other neuronal populations in cortex, hippocampus, and substantia nigra. Recombined Purkinje neurons differ in their miRNA profile from their nonrecombined counterparts, indicating physiological significance. These observations reveal the existence of a previously unrecognized mechanism to communicate RNA-based signals between the hematopoietic system and various organs, including the brain, in response to inflammation.

Published
2014

48. Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation

Author

Ridder, Kirsten, primary, Keller, Sascha, additional, Dams, Maria, additional, Rupp, Anne-kathleen, additional, Schlaudraff, Jessica, additional, Del Turco, Domenico, additional, Starmann, Julia, additional, Macas, Jadranka, additional, Karpova, Darja, additional, Devraij, Kavi, additional, Depboylu, Candan, additional, Landfried, Britta, additional, Arnold, Bernd, additional, Plate, Karl H., additional, Höglinger, Günter, additional, Sültmann, Holger, additional, Altevogt, Peter, additional, and Momma, Stefan, additional

Published
2014
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