Hematopoietic stem and progenitor cells (HSPCs) are responsible for the production of blood and immune cells. Throughout life, HSPCs acquire oncogenic aberrations that can cause hematological cancers. Although molecular programs maintaining stem cell integrity have been identified, safety mechanisms eliminating malignant HSPCs from the stem cell pool remain poorly characterized. Here, we show that HSPCs constitutively present antigens via major histocompatibility complex class II. The presentation of immunogenic antigens, as occurring during malignant transformation, triggers bidirectional interactions between HSPCs and antigen-specific CD4⁺ T cells, causing stem cell proliferation, differentiation, and specific exhaustion of aberrant HSPCs. This immunosurveillance mechanism effectively eliminates transformed HSPCs from the hematopoietic system, thereby preventing leukemia onset. Together, our data reveal a bidirectional interaction between HSPCs and CD4⁺ T cells, demonstrating that HSPCs are not only passive receivers of immunological signals but also actively engage in adaptive immune responses to safeguard the integrity of the stem cell pool.

Further Reading:

https://www.dkfz.de/en/presse/pressemitteilungen/2022/dkfz-pm-22-28c-How-blood-stem-cells-stay-intact-for-a-lifetime.php

Publication

Hernández-Malmierca P, Vonficht D, Schnell A, Uckelmann HJ, Bollhagen A, Mahmoud MAA, Landua SL, van der Salm E, Trautmann CL, Raffel S, Grünschläger F, Lutz R, Ghosh M, Renders S, Correia N, Donato E, Dixon KO, Hirche C, Andresen C, Robens C, Werner PS, Boch T, Eisel D, Osen W, Pilz F, Przybylla A, Klein C, Buchholz F, Milsom MD, Essers MAG, Eichmüller SB, Hofmann WK, Nowak D, Hübschmann D, Hundemer M, Thiede C, Bullinger L, Müller-Tidow C, Armstrong SA, Trumpp A, Kuchroo VK, Haas S. Antigen presentation safeguards the integrity of the hematopoietic stem cell pool. Cell Stem Cell. 2022 May 5;29(5):760-775.e10. doi:10.1016/j.stem.2022.04.007 PMID: 35523139.

A new method called MutaSeq allows stem cells and cancer stem cells to be studied at the single cell level and the resulting cell clones to be traced directly. The method was developed by scientists from HI-STEM, the German Cancer Research Center (DKFZ), the European Molecular Biology Laboratory (EMBL) and the Center for Genome Regulation in Barcelona. Studying thousands of individual cells in parallel, the researchers combined the analysis of the genomic cancer mutations with the associated expression profiles.

Further Reading:

• Publication: Velten L, Story BA, Hernández-Malmierca P, Raffel S, Leonce DR, Milbank J, Paulsen M, Demir A, Szu-Tu C, Frömel R, Lutz C, Nowak D, Jann JC, Pabst C, Boch T, Hofmann WK, Müller-Tidow C, Trumpp A, Haas S, Steinmetz LM. Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics. Nature Communication. 2021 Mar 1;12(1):1366. doi: 10.1038/s41467-021-21650-1. PMID: 33649320; PMCID: PMC7921413.
• DKFZ Press Release

The LeukoSyStem consortium, which is coordinated by HI-STEM group leader Simon Haas, investigates leukaemia stem cells in acute myeloid leukaemia (AML). The German Federal Ministry of Education and Research (BMBF) financially supports this collaboration with a total sum of €2.45 M for five years as part of its eMED program on systems medicine. LeukoSystem is a collaboration between junior researchers, namely Dr. Simon Raffel (Heidelberg University Hospital), Lars Velten (CRG Barcelona), Laleh Haghverdi (EMBL Heidelberg) and Simon Haas (HI-STEM gGmbH and German Cancer Research Center (DKFZ)).

The aim of their project is to investigate the cells that are the origin of acute myeloid leukaemia (AML) and thus "get to the root of the problem". The scientists intend to use isolated single cells from patient samples to investigate characteristic markers, mutations, functional data, and metabolic pathways, to gain a better understanding of leukaemia stem cells and their environment in the bone marrow. The collected data will be evaluated comprehensively with the help of computer algorithms specially developed for the purpose.

Read more:

• DKFZ Press Release
• Press Release Heidelberg University Hospital (in German)
• EMBL News
• Haas Lab: Stem Cells at the Interface of Hematopoiesis, Immunity and Cancer

The lastest paper from the group of Simon Haas was published by Nature Cell Biology shortly before Christmas last year. This is the result of a great team effort together with colleagues at the DKFZ and HI-STEM.

The published methods are able to reveal the three-dimensional organization of the bone marrow at the single cell level. Using this approach the teams have identified previously unknown cell types that create specific local environments required for blood generation from stem cells. The study reveals an unexpected complexity of the bone marrow and its microdomains at an unprecedented resolution and provides a novel scientific basis to study blood diseases such as leukemias.

Read more:

• Original Paper: Baccin, C.*, Al-Sabah*, J., Velten, L.*@, Helbling, P. M., Grunschlager, F., Hernandez-Malmierca, P., Nombela-Arrieta, C., Steinmetz, L. M.@, Trumpp, A.@, & Haas, S.@ (2019). Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nature Cell Biology. doi: 10.1038/s41556-019-0439-6*: Shared first authors, @ Joint Supervising authors
• News and Views Article: Lucas, D., Salomonis, N., & Grimes, H. L. (2019). Unraveling bone marrow architecture. Nat Cell Biol. doi: 10.1038/s41556-019-0447-6
• DKFZ Press Release
• EMBL Press Release

Classically, stem and progenitor populations have been considered discrete homogeneous populations. However, recent technological advances have revealed significant hematopoietic stem cell (HSC) heterogeneity, with evidence for early HSC lineage segregation and the presence of lineage-biased HSCs and lineage-restricted progenitors within the HSC compartment. These and other findings challenge many aspects of the classical view of HSC biology.

In our recent review in Cell Stem Cell, we analyse the most recent findings regarding the causes and consequences of HSC heterogeneity, discuss their far-reaching implications, and suggest that so-called continuum-based models may help consolidate apparently divergent experimental observations in this field.

Read more:

• Haas, S., Trumpp, A., & Milsom, M.D. (2018). Causes and Consequences of Hematopoietic Stem Cell Heterogeneity. Cell Stem Cell, 22(5), 627-638. doi: 10.1016/j.stem.2018.04.003
• Direct Access to the article (valid until June 22, 2018): https://authors.elsevier.com/a/1W~i~6tu0CU9VO

Two awards at once, both carrying high monetary prizes, go to two HI-STEM members: Simon Raffel will receive the 2017 Walter Schulz Prize for his discovery how misregulated breakdown of amino acids in leukemia stem cells promotes blood cancer. To find out more about this work, read our news feature.

Simon Haas will share the 2018 Otto Schmeil Prize with his colleague Lars Velten from EMBL. The two stem cell researchers have jointly demonstrated that the development of blood cells in the bone marrow follows very different paths from what scientists have assumed up to now.

 Read more:

• DKFZ Press Release
• Otto-Schmeil-Preis
• Walter-Schulz Forschungspreis

The Boehringer Ingelheim Foundation has awarded a travel grant to Simon Haas for visiting research at Harvard Medical School.

Human haematopoietic stem cell lineage commitment is a continuous process (Nature Cell Biology, 2017)

Read more: Human haematopoietic stem cell lineage commitment is a continuous process (Nature Cell Biology,...