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1. The emergence and early fate decisions of stem and progenitor cells in the haematopoietic system

Author

Lutteropp, Michael and Jacobsen, Sten Eirik

Subjects
616.02774, Haematology, Biology (medical sciences), Stem cells (clinical sciences), Molecular haematology, Blood, Medical Sciences, Clinical laboratory sciences, haematopoiesis, stem cells, lineage commitment
Abstract

The alternative road map describes the separation of lympho-myeloid and myeloid-megakaryocyte-erythroid (myeloid-Mk-E) lineages as the earliest haematopoietic commitment event. However, a number of aspects of this lineage restriction process remain poorly understood. Herein this work identified a lympho-myeloid restricted progenitor in the embryo, which resembles the adult LMPP, and demonstrated that lymphoid lineage restriction is initiated prior to definitive haematopoiesis, much earlier than previously appreciated. In vivo fate mapping showed that lympho-myeloid progenitors significantly contribute to steady state myelopoiesis in the embryo. The early thymic progenitor (ETP) as most primitive cell in the thymus was characterised and demonstrated to sustain B, T and myeloid but not Mk potentials at the single cell level. The ETP therefore largely resembles the cellular properties of lympho-myeloid progenitors in bone marrow and foetal liver, which points to these cells as candidate thymus seeding progenitors (TSP). Furthermore the existence of a putative Mk progenitor was explored within the LSKCD150+CD48+Gata1pos compartment of a Gata1 reporter mouse providing the basis for a future prospective characterisation. Finally, this work evaluated the earliest lineage restriction of von Willebrand factor (Vwf)-EGFP+ and EGFP- haematopoietic stem cells (HSCs) through in vitro paired daughter fate mapping. Single Vwf+ HSCs showed heterogeneous Mk priming and more frequently sustained Mk potential after cell division. Moreover, analysis of lineage priming between daughter cells revealed the asymmetric expression of key lineage determinants and stem cell regulators, which might be employed as reporters for future fate mapping studies.

Published
2012

2. Data from Preclinical Assessment of a MUC12-Targeted BiTE (Bispecific T-cell Engager) Molecule

Author

Pham, Elizabeth, primary, Friedrich, Matthias, primary, Aeffner, Famke, primary, Lutteropp, Michael, primary, Mariano, Natalie F., primary, Deegen, Petra, primary, Dahlhoff, Christoph, primary, Vogel, Franziska, primary, Bluemel, Claudia, primary, Harrold, John M., primary, Brandl, Christian, primary, Grinberg, Natalia, primary, Rattel, Benno, primary, Coxon, Angela, primary, and Bailis, Julie M., primary

Published
2023
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3. Supplementary Data from Preclinical Assessment of a MUC12-Targeted BiTE (Bispecific T-cell Engager) Molecule

Author

Pham, Elizabeth, primary, Friedrich, Matthias, primary, Aeffner, Famke, primary, Lutteropp, Michael, primary, Mariano, Natalie F., primary, Deegen, Petra, primary, Dahlhoff, Christoph, primary, Vogel, Franziska, primary, Bluemel, Claudia, primary, Harrold, John M., primary, Brandl, Christian, primary, Grinberg, Natalia, primary, Rattel, Benno, primary, Coxon, Angela, primary, and Bailis, Julie M., primary

Published
2023
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4. Immune checkpoints PVR and PVRL2 are prognostic markers in AML and their blockade represents a new therapeutic option

Author

Stamm, Hauke, Klingler, Felix, Grossjohann, Eva-Maria, Muschhammer, Jana, Vettorazzi, Eik, Heuser, Michael, Mock, Ulrike, Thol, Felicitas, Vohwinkel, Gabi, Latuske, Emily, Bokemeyer, Carsten, Kischel, Roman, Dos Santos, Cedric, Stienen, Sabine, Friedrich, Matthias, Lutteropp, Michael, Nagorsen, Dirk, Wellbrock, Jasmin, and Fiedler, Walter

Published
2018
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7. Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy

Author

Sanjuan-Pla, Alejandra, Macaulay, Iain C., Jensen, Christina T., Woll, Petter S., Luis, Tiago C., Mead, Adam, Moore, Susan, Carella, Cintia, Matsuoka, Sahoko, Jones, Tiphaine Bouriez, Chowdhury, Onima, Stenson, Laura, Lutteropp, Michael, Green, Joanna C.A., Facchini, Raffaella, Boukarabila, Hanane, Grover, Amit, Gambardella, Adriana, Thongjuea, Supat, Carrelha, Joana, Tarrant, Paul, Atkinson, Deborah, Clark, Sally-Ann, Nerlov, Claus, and Jacobsen, Sten Eirik W.

Subjects
Hematopoiesis -- Physiological aspects -- Genetic aspects -- Research, Hematopoietic stem cells -- Physiological aspects -- Research, Blood platelets -- Physiological aspects -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The blood system is maintained by a small pool of haematopoietic stem cells (HSCs), which are required and sufficient for replenishing all human blood cell lineages at millions of cells per second throughout life. Megakaryocytes in the bone marrow are responsible for the continuous production of platelets in the blood, crucial for preventing bleeding--a common and life-threatening side effect of many cancer therapies--and major efforts are focused at identifying the most suitable cellular and molecular targets to enhance platelet production after bone marrow transplantation or chemotherapy (1). Although it has become clear that distinct HSC subsets exist that are stably biased towards the generation of lymphoid or myeloid blood cells (2-4), we are yet to learn whether other types of lineage-biased HSC exist or understand their inter-relationships and how differently lineage-biased HSCs are generated and maintained. The functional relevance of notable phenotypic and molecular similarities between megakaryocytes and bone marrow cells with an HSC cell-surface phenotype (5-8) remains unclear. Here we identify and prospectively isolate a molecularly and functionally distinct mouse HSC subset primed for platelet-specific gene expression, with enhanced propensity for short- and long-term reconstitution of platelets. Maintenance of platelet-biased HSCs crucially depends on thrombopoietin, the primary extrinsic regulator of platelet development (9). Platelet-primed HSCs also frequently have a long-term myeloid lineage bias, can self-renew and give rise to lymphoid-biased HSCs. These findings show that HSC subtypes can be organized into a cellular hierarchy, with platelet-primed HSCs at the apex. They also demonstrate that molecular and functional priming for platelet development initiates already in a distinct HSC population. The identification of a platelet-primed HSC population should enable the rational design of therapies enhancing platelet output., One of the megakaryocyte genes most highly expressed in mouse HSC-enriched bone marrow cells is that encoding von Willebrand factor (vWF) (7,10), a protein involved in platelet aggregation (11) and [...]

Published
2013

8. Preclinical Assessment of a MUC12-Targeted BiTE (Bispecific T-cell Engager) Molecule

Author

Pham, Elizabeth, primary, Friedrich, Matthias, additional, Aeffner, Famke, additional, Lutteropp, Michael, additional, Mariano, Natalie F., additional, Deegen, Petra, additional, Dahlhoff, Christoph, additional, Vogel, Franziska, additional, Bluemel, Claudia, additional, Harrold, John M., additional, Brandl, Christian, additional, Grinberg, Natalia, additional, Rattel, Benno, additional, Coxon, Angela, additional, and Bailis, Julie M., additional

Published
2021
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9. Additional file 1: of CD33/CD3-bispecific T-cell engaging (BiTE®) antibody construct targets monocytic AML myeloid-derived suppressor cells

Author

Jitschin, Regina, Saul, Domenica, Braun, Martina, Sehmus Tohumeken, Völkl, Simon, Kischel, Roman, Lutteropp, Michael, Santos, Cedric Dos, Mackensen, Andreas, and Mougiakakos, Dimitrios

Subjects
immune system diseases, chemical and pharmacologic phenomena, hemic and immune systems
Abstract

Table S1. Fluorochrome-coupled antibodies and/or chemical dyes for flow cytometry. Table S2. AML-derived PBMCs (n=12) were treated with AMG 330 for three days. The median fluorescence intensity (MFI) of granzyme B (Grz B), CD107, perforin, CD69, CD137, CD25, CD154, IL2, IFNγ, and the cells’ expansion index was assessed by FACS in CD4+/CD8+ CD3+ T-cells as indicated. The association between those variables and the PBMCs’ initial frequency of HLA-DRlo cells among CD14+ cells was calculated using a Pearson correlation analysis. Abbreviations: p, p-value; r, Pearson correlation. Table S3. AML-derived PBMCs (n=12) were treated with AMG 330 for three days. The median fluorescence intensity (MFI) of granzyme B (Grz B), CD107, perforin, CD69, CD137, CD25, CD154, IL2, and IFNγ was assessed by FACS in CD4+/CD8+ CD3+ T-cells. The association between those variables and the PBMCs’ initial frequency of CD3+ T-cells was calculated using a Pearson correlation analysis. Abbreviations: p, p-value; r, Pearson correlation. (DOCX 50 kb)

Published
2018
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10. Embryonic thymopoiesis is initiated by an immune-restricted lympho-myeloid progenitor, independently of notch signaling

Author

Luis, Tiago, primary, Luc, Sidinh, additional, Mizukami, Takuo, additional, Boukarabila, Hanane, additional, Thongjuea, Supat, additional, Woll, Petter, additional, Azzoni, Emanuele, additional, Giustacchini, Alice, additional, Lutteropp, Michael, additional, Bouriez-Jones, Tiphaine, additional, Vaidya, Harsh, additional, Mead, Adam, additional, Atkinson, Deborah, additional, Boiers, Charlotta, additional, Carrelha, Joana, additional, Macaulay, Iain, additional, Patient, Roger, additional, Geissmann, Frederic, additional, Nerlov, Claus, additional, Sandberg, Rickard, additional, de Bruijn, Marella, additional, Blackburn, Clare, additional, Godin, Isabelle, additional, and Jacobsen, Sten Eirik, additional

Published
2017
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11. Initial seeding of the embryonic thymus by immune-restricted lympho-myeloid progenitors

Author

Luis, Tiago C, primary, Luc, Sidinh, additional, Mizukami, Takuo, additional, Boukarabila, Hanane, additional, Thongjuea, Supat, additional, Woll, Petter S, additional, Azzoni, Emanuele, additional, Giustacchini, Alice, additional, Lutteropp, Michael, additional, Bouriez-Jones, Tiphaine, additional, Vaidya, Harsh, additional, Mead, Adam J, additional, Atkinson, Deborah, additional, Böiers, Charlotta, additional, Carrelha, Joana, additional, Macaulay, Iain C, additional, Patient, Roger, additional, Geissmann, Frederic, additional, Nerlov, Claus, additional, Sandberg, Rickard, additional, de Bruijn, Marella F T R, additional, Blackburn, C Clare, additional, Godin, Isabelle, additional, and Jacobsen, Sten Eirik W, additional

Published
2016
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12. Embryonic thymopoiesis is initiated by an immune-restricted lympho-myeloid progenitor independently of notch signaling

Author

Luis, Tiago Cunha, primary, Luc, Sidinh, additional, Mizukami, Takuo, additional, Boukarabila, Hanane, additional, Thongjuea, Supat, additional, Woll, Petter, additional, Azzoni, Emanuele, additional, Lutteropp, Michael, additional, Bouriez-Jones, Tiphaine, additional, Vaidya, Harsh, additional, Mead, Adam, additional, Atkinson, Deborah, additional, Böiers, Charlotta, additional, Carrelha, Joana, additional, Macaulay, Iain, additional, Patient, Roger, additional, Nerlov, Claus, additional, Sandberg, Rickard, additional, de Bruijn, Marella, additional, Blackburn, C. Clare, additional, Godin, Isabelle, additional, and Jacobsen, Sten Eirik, additional

Published
2016
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13. Expression of Novel Immune Checkpoint Molecules PVR and PVRL2 Confers a Negative Prognosis to Patients with Acute Myeloid Leukemia and Their Blockade Augments T-Cell Mediated Lysis of AML Cells Alone or in Combination with the BiTE® Antibody Construct AMG 330

Author

Stamm, Hauke, primary, Klingler, Felix, additional, Pende, Daniela, additional, Vettorazzi, Eik, additional, Heuser, Michael, additional, Mock, Ulrike, additional, Bokemeyer, Carsten, additional, Kischel, Roman, additional, Stienen, Sabine, additional, Friedrich, Matthias, additional, Lutteropp, Michael, additional, Nagorsen, Dirk, additional, Wellbrock, Jasmin, additional, and Fiedler, Walter, additional

Published
2015
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15. FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors.

Author

UCL - SSS/DDUV - Institut de Duve, Mead, Adam J, Kharazi, Shabnam, Atkinson, Deborah, Macaulay, Iain, Pecquet, Christian, Loughran, Stephen, Lutteropp, Michael, Woll, Petter, Chowdhury, Onima, Luc, Sidinh, Buza-Vidas, Natalija, Ferry, Helen, Clark, Sally-Ann, Goardon, Nicolas, Vyas, Paresh, Constantinescu, Stefan N., Sitnicka, Ewa, Nerlov, Claus, Jacobsen, Sten Eirik W, UCL - SSS/DDUV - Institut de Duve, Mead, Adam J, Kharazi, Shabnam, Atkinson, Deborah, Macaulay, Iain, Pecquet, Christian, Loughran, Stephen, Lutteropp, Michael, Woll, Petter, Chowdhury, Onima, Luc, Sidinh, Buza-Vidas, Natalija, Ferry, Helen, Clark, Sally-Ann, Goardon, Nicolas, Vyas, Paresh, Constantinescu, Stefan N., Sitnicka, Ewa, Nerlov, Claus, and Jacobsen, Sten Eirik W

Abstract

Whether signals mediated via growth factor receptors (GFRs) might influence lineage fate in multipotent progenitors (MPPs) is unclear. We explored this issue in a mouse knockin model of gain-of-function Flt3-ITD mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. When expressed in MPPs, Flt3-ITD collaborated with Runx1 mutation to induce high-penetrance aggressive leukemias that were exclusively of the myeloid phenotype. Flt3-ITDs preferentially expanded MPPs with reduced lymphoid and increased myeloid transcriptional priming while compromising early B and T lymphopoiesis. Flt3-ITD-induced myeloid lineage bias involved upregulation of the transcription factor Pu.1, which is a direct target gene of Stat3, an aberrantly activated target of Flt3-ITDs, further establishing how lineage bias can be inflicted on MPPs through aberrant GFR signaling. Collectively, these findings provide new insights into how oncogenic mutations might subvert the normal process of lineage commitment and dictate the phenotype of resulting malignancies.

Published
2013

16. Lymphomyeloid contribution of an immune-restricted progenitor emerging prior to definitive hematopoietic stem cells

Author

Böiers, C, Carrelha, J, Lutteropp, M, Luc, S, Green, J, Azzoni, E, Woll, P, Mead, A, Hultquist, A, Swiers, G, Perdiguero, E, Macaulay, I, Melchiori, L, Luis, T, Kharazi, S, Bouriez-Jones, T, Deng, Q, Pontén, A, Atkinson, D, Jensen, C, Sitnicka, E, Geissmann, F, Godin, I, Sandberg, R, de Bruijn, M, Jacobsen, S, Böiers, Charlotta, Carrelha, Joana, Lutteropp, Michael, Luc, Sidinh, Green, Joanna C A, Azzoni, Emanuele, Woll, Petter S, Mead, Adam J, Hultquist, Anne, Swiers, Gemma, Perdiguero, Elisa Gomez, Macaulay, Iain C, Melchiori, Luca, Luis, Tiago C, Kharazi, Shabnam, Bouriez-Jones, Tiphaine, Deng, Qiaolin, Pontén, Annica, Atkinson, Deborah, Jensen, Christina T, Sitnicka, Ewa, Geissmann, Frederic, Godin, Isabelle, Sandberg, Rickard, de Bruijn, Marella F T R, Jacobsen, Sten Eirik W, Böiers, C, Carrelha, J, Lutteropp, M, Luc, S, Green, J, Azzoni, E, Woll, P, Mead, A, Hultquist, A, Swiers, G, Perdiguero, E, Macaulay, I, Melchiori, L, Luis, T, Kharazi, S, Bouriez-Jones, T, Deng, Q, Pontén, A, Atkinson, D, Jensen, C, Sitnicka, E, Geissmann, F, Godin, I, Sandberg, R, de Bruijn, M, Jacobsen, S, Böiers, Charlotta, Carrelha, Joana, Lutteropp, Michael, Luc, Sidinh, Green, Joanna C A, Azzoni, Emanuele, Woll, Petter S, Mead, Adam J, Hultquist, Anne, Swiers, Gemma, Perdiguero, Elisa Gomez, Macaulay, Iain C, Melchiori, Luca, Luis, Tiago C, Kharazi, Shabnam, Bouriez-Jones, Tiphaine, Deng, Qiaolin, Pontén, Annica, Atkinson, Deborah, Jensen, Christina T, Sitnicka, Ewa, Geissmann, Frederic, Godin, Isabelle, Sandberg, Rickard, de Bruijn, Marella F T R, and Jacobsen, Sten Eirik W

Abstract

In jawed vertebrates, development of an adaptive immune-system is essential for protection of the born organism against otherwise life-threatening pathogens. Myeloid cells of the innate immune system are formed early in development, whereas lymphopoiesis has been suggested to initiate much later, following emergence of definitive hematopoietic stem cells (HSCs). Herein, we demonstrate that the embryonic lymphoid commitment process initiates earlier than previously appreciated, prior to emergence of definitive HSCs, through establishment of a previously unrecognized entirely immune-restricted and lymphoid-primed progenitor. Notably, this immune-restricted progenitor appears to first emerge in the yolk sac and contributes physiologically to the establishment of lymphoid and some myeloid components of the immune-system, establishing the lymphomyeloid lineage restriction process as an early and physiologically important lineage-commitment step in mammalian hematopoiesis

Published
2013

17. FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors

Author

Mead, Adam J., Kharazi, Shabnam, Atkinson, Deborah, Macaulay, Iain, Pecquet, Christian, Loughran, Stephen, Lutteropp, Michael, Woll, Petter, Chowdhury, Onima, Luc, Sidinh, Buza-Vidas, Natalija, Ferry, Helen, Clark, Sally-Ann, Goardon, Nicolas, Vyas, Paresh, Constantinescu, Stefan N., Sitnicka Quinn, Ewa, Nerlov, Claus, Jacobsen, Sten Eirik W., Mead, Adam J., Kharazi, Shabnam, Atkinson, Deborah, Macaulay, Iain, Pecquet, Christian, Loughran, Stephen, Lutteropp, Michael, Woll, Petter, Chowdhury, Onima, Luc, Sidinh, Buza-Vidas, Natalija, Ferry, Helen, Clark, Sally-Ann, Goardon, Nicolas, Vyas, Paresh, Constantinescu, Stefan N., Sitnicka Quinn, Ewa, Nerlov, Claus, and Jacobsen, Sten Eirik W.

Abstract

Whether signals mediated via growth factor receptors (GFRs) might influence lineage fate in multipotent progenitors (MPPs) is unclear. We explored this issue in a mouse knockin model of gain-of-function Flt3-ITD mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. When expressed in MPPs, Flt3-ITD collaborated with Runx1 mutation to induce high-penetrance aggressive leukemias that were exclusively of the myeloid phenotype. Flt3-ITDs preferentially expanded MPPs with reduced lymphoid and increased myeloid transcriptional priming while compromising early B and T lymphopoiesis. Flt3-ITD-induced myeloid lineage bias involved upregulation of the transcription factor Pu.1, which is a direct target gene of Stat3, an aberrantly activated target of Flt3-ITDs, further establishing how lineage bias can be inflicted on MPPs through aberrant GFR signaling. Collectively, these findings provide new insights into how oncogenic mutations might subvert the normal process of lineage commitment and dictate the phenotype of resulting malignancies.

Published
2013

18. Lymphomyeloid Contribution of an Immune-Restricted Progenitor Emerging Prior to Definitive Hematopoietic Stem Cells

Author

Böiers, Charlotta, primary, Carrelha, Joana, additional, Lutteropp, Michael, additional, Luc, Sidinh, additional, Green, Joanna C.A., additional, Azzoni, Emanuele, additional, Woll, Petter S., additional, Mead, Adam J., additional, Hultquist, Anne, additional, Swiers, Gemma, additional, Perdiguero, Elisa Gomez, additional, Macaulay, Iain C., additional, Melchiori, Luca, additional, Luis, Tiago C., additional, Kharazi, Shabnam, additional, Bouriez-Jones, Tiphaine, additional, Deng, Qiaolin, additional, Pontén, Annica, additional, Atkinson, Deborah, additional, Jensen, Christina T., additional, Sitnicka, Ewa, additional, Geissmann, Frederic, additional, Godin, Isabelle, additional, Sandberg, Rickard, additional, de Bruijn, Marella F.T.R., additional, and Jacobsen, Sten Eirik W., additional

Published
2013
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19. Establishment of lympho-myeloid restricted progenitors prior to the emergence of definitive hematopoietic stem cells

Author

Böiers, Charlotta, primary, Lutteropp, Michael, additional, Luc, Sidinh, additional, Woll, Petter, additional, Mead, Adam, additional, Hultquist, Anne, additional, Carrelha, Joana, additional, Macaulay, Iain, additional, Swiers, Gemma, additional, Melchiori, Luca, additional, Luis, Tiago, additional, Kharazi, Shabnam, additional, Bouriez-Jones, Tiphaine, additional, Deng, Qiaolin, additional, Pontén, Annica, additional, Jensen, Christina, additional, Sitnicka, Ewa, additional, Sandberg, Rickard, additional, de Bruijn, Marella, additional, and Jacobsen, Sten Eirik, additional

Published
2013
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20. FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors

Author

Mead, Adam J., primary, Kharazi, Shabnam, additional, Atkinson, Deborah, additional, Macaulay, Iain, additional, Pecquet, Christian, additional, Loughran, Stephen, additional, Lutteropp, Michael, additional, Woll, Petter, additional, Chowdhury, Onima, additional, Luc, Sidinh, additional, Buza-Vidas, Natalija, additional, Ferry, Helen, additional, Clark, Sally-Ann, additional, Goardon, Nicolas, additional, Vyas, Paresh, additional, Constantinescu, Stefan N., additional, Sitnicka, Ewa, additional, Nerlov, Claus, additional, and Jacobsen, Sten Eirik W., additional

Published
2013
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21. The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential

Author

Luc, Sidinh, primary, Luis, Tiago C, additional, Boukarabila, Hanane, additional, Macaulay, Iain C, additional, Buza-Vidas, Natalija, additional, Bouriez-Jones, Tiphaine, additional, Lutteropp, Michael, additional, Woll, Petter S, additional, Loughran, Stephen J, additional, Mead, Adam J, additional, Hultquist, Anne, additional, Brown, John, additional, Mizukami, Takuo, additional, Matsuoka, Sahoko, additional, Ferry, Helen, additional, Anderson, Kristina, additional, Duarte, Sara, additional, Atkinson, Deborah, additional, Soneji, Shamit, additional, Domanski, Aniela, additional, Farley, Alison, additional, Sanjuan-Pla, Alejandra, additional, Carella, Cintia, additional, Patient, Roger, additional, de Bruijn, Marella, additional, Enver, Tariq, additional, Nerlov, Claus, additional, Blackburn, Clare, additional, Godin, Isabelle, additional, and Jacobsen, Sten Eirik W, additional

Published
2012
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22. FLT3-ITDs Introduce a Myeloid Differentiation and Transformation Bias to Multipotent Lympho-Myeloid Progenitors

Author

Mead, Adam J., primary, Kharazi, Shabnam, additional, Macaulay, Iain C, additional, Atkinson, Debbie, additional, Loughran, Stephen, additional, Lutteropp, Michael, additional, Woll, Petter, additional, Luc, Sidinh, additional, Buza-Vidas, Natalija, additional, Ferry, Helen, additional, Nerlov, Claus, additional, Sitnicka, Ewa, additional, and Jacobsen, Sten Eirik W., additional

Published
2011
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23. The Earliest Thymic T Cell Progenitors Sustain B Cell and Myeloid Lineage Potentials

Author

Luc, Sidinh, primary, Macaulay, Iain C, additional, Buza-Vidas, Natalija, additional, Bouriez-Jones, Tiphaine, additional, Lutteropp, Michael, additional, Woll, Petter, additional, Mead, Adam J., additional, Boukarabila, Hanane, additional, Luis, Tiago C, additional, Mizukami, Takuo, additional, Matsuoka, Sahoko, additional, Brown, John, additional, Ferry, Helen, additional, Anderson, Kristina, additional, Duarte, Sara, additional, Atkinson, Deborah, additional, Soneji, Shamit, additional, Domanski, Aniela, additional, Farley, Alison, additional, Sanjuan-Pla, Alejandra, additional, Carella, Cintia, additional, Patient, Roger, additional, de Bruijn, Marella, additional, Enver, Tariq, additional, Nerlov, Claus, additional, Blackburn, Clare, additional, Godin, Isabelle, additional, and Jacobsen, Sten Eirik W, additional

Published
2011
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25. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance

Author

Mortensen, Monika, primary, Soilleux, Elizabeth J., additional, Djordjevic, Gordana, additional, Tripp, Rebecca, additional, Lutteropp, Michael, additional, Sadighi-Akha, Elham, additional, Stranks, Amanda J., additional, Glanville, Julie, additional, Knight, Samantha, additional, Jacobsen, Sten-Eirik W., additional, Kranc, Kamil R., additional, and Simon, Anna Katharina, additional

Published
2011
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26. Selective Persistence of Distinct Stem/B Leukaemic Stem Cells In Childhood Acute Lymphoblastic Leukaemia In Clinical Remission.

Author

Lutz, Christoph, primary, Woll, Petter, additional, Castor, Anders, additional, Ferry, Helen, additional, Jensen, Christina, additional, Green, Joanne, additional, Dreau, Helene, additional, Lutteropp, Michael, additional, Schuh, Anna, additional, Hall, Georgina, additional, Mitchell, Chris, additional, Zuna, Jan, additional, Buckle, Veronica, additional, Jacobsen, Sten Eirik W, additional, and Enver, Tariq, additional

Published
2010
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27. Diceris selectively important for the earliest stages of erythroid development

Author

Buza-Vidas, Natalija, Cismasiu, Valeriu B., Moore, Susan, Mead, Adam J., Woll, Petter S., Lutteropp, Michael, Melchiori, Luca, Luc, Sidinh, Bouriez-Jones, Tiphaine, Atkinson, Deborah, O'Carroll, Donal, Jacobsen, Sten Eirik W., and Nerlov, Claus

Abstract

MicroRNAs (miRs) are involved in many aspects of normal and malignant hematopoiesis, including hematopoietic stem cell (HSC) self-renewal, proliferation, and terminal differentiation. However, a role for miRs in the generation of the earliest stages of lineage committed progenitors from HSCs has not been identified. Using Dicerinactivation, we show that the miR complex is not only essential for HSC maintenance but is specifically required for their erythroid programming and subsequent generation of committed erythroid progenitors. In bipotent pre-MegEs, loss of Dicerup-regulated transcription factors preferentially expressed in megakaryocyte progenitors (Gata2and Zfpm1) and decreased expression of the erythroid-specific Klf1transcription factor. These results show a specific requirement for Dicerin acquisition of erythroid lineage programming and potential in HSCs and their subsequent erythroid lineage differentiation, and in particular indicate a role for the miR complex in achieving proper balance of lineage-specific transcriptional regulators necessary for HSC multilineage potential to be maintained.

Published
2012
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28. An Innovative Approach to Optimize First-In-Human Minimal Anticipated Biological Effect Level Based Starting Dose in Oncology Trials for Bispecific T-Cell Engagers: Experience from A Solid Tumor Bispecific T-Cell Engager.

Author

Zhou D, Kischel R, Stienen S, Townsley D, Sternjak A, Lutteropp M, Bailis J, Friedrich M, Rattel B, Mehta K, and Upreti VV

Abstract

Bispecific T-cell engagers (Bi-TCEs) have revolutionized the treatment and management of both hematological and solid tumor indications with opportunities to become best-in-class therapeutics for cancer. However, defining the dose and dosing regimen for the first-in-human (FIH) studies of Bi-TCEs can be challenging, as a high starting dose can expose subjects to serious toxicity while a low starting dose based on traditional minimal anticipated biological effect level (MABEL) approach could lead to lengthy dose escalations that exposes seriously ill patients to sub-therapeutic dosing. Leveraging our in-depth and broad clinical development experience across three generations of Bi-TCEs across both liquid and solid tumor indications, we developed an innovative modified MABEL approach for starting dose selection that integrates knowledge based on the target biology, indication, toxicology, in vitro, in vivo pharmacological evaluations, and translational pharmacokinetic/pharmacodynamic (PK/PD) modeling, together with anticipated safety profile. Compared to the traditional MABEL approach in which high effector to target (E:T) cell ratios are typically used, our innovative approach utilized an optimized E:T cell ratio that better reflects the tumor microenvironment. This modified MABEL approach was successfully applied to FIH dose selection for a half-life extended (HLE) Bi-TCE for gastric cancer. This modified MABEL approach enabled a 10-fold higher starting dose that was deemed safe and well tolerated and saved at least two dose-escalation cohorts before reaching the projected efficacious dose. This approach was successfully accepted by global regulatory agencies and can be applied for Bi-TCEs across both hematological and solid tumor indications for accelerating the clinical development for Bi-TCEs., (© 2024 Amgen. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Published
2024
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29. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance.

Author

Mortensen M, Soilleux EJ, Djordjevic G, Tripp R, Lutteropp M, Sadighi-Akha E, Stranks AJ, Glanville J, Knight S, Jacobsen SE, Kranc KR, and Simon AK

Subjects
Animals, Apoptosis physiology, Autophagy-Related Protein 7, Cell Proliferation, DNA Damage physiology, Female, Male, Mice, Mice, Knockout, Microtubule-Associated Proteins genetics, Mitochondria physiology, Myeloproliferative Disorders physiopathology, Reactive Oxygen Species metabolism, Stem Cells physiology, Autophagy physiology, Hematopoietic Stem Cells physiology, Microtubule-Associated Proteins physiology
Abstract

The role of autophagy, a lysosomal degradation pathway which prevents cellular damage, in the maintenance of adult mouse hematopoietic stem cells (HSCs) remains unknown. Although normal HSCs sustain life-long hematopoiesis, malignant transformation of HSCs leads to leukemia. Therefore, mechanisms protecting HSCs from cellular damage are essential to prevent hematopoietic malignancies. In this study, we crippled autophagy in HSCs by conditionally deleting the essential autophagy gene Atg7 in the hematopoietic system. This resulted in the loss of normal HSC functions, a severe myeloproliferation, and death of the mice within weeks. The hematopoietic stem and progenitor cell compartment displayed an accumulation of mitochondria and reactive oxygen species, as well as increased proliferation and DNA damage. HSCs within the Lin(-)Sca-1(+)c-Kit(+) (LSK) compartment were significantly reduced. Although the overall LSK compartment was expanded, Atg7-deficient LSK cells failed to reconstitute the hematopoietic system of lethally irradiated mice. Consistent with loss of HSC functions, the production of both lymphoid and myeloid progenitors was impaired in the absence of Atg7. Collectively, these data show that Atg7 is an essential regulator of adult HSC maintenance.

Published
2011
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