bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024‒03‒24
sixteen papers selected by
William Grey, University of York
  1. Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes.
  2. Abcb10 regulates murine hematopoietic stem cell potential and erythroid differentiation.
  3. Ex vivo culture resting time impacts transplantation outcomes of genome-edited human hematopoietic stem and progenitor cells in xenograft mouse models.
  4. Loss of Dnmt3a increased self-renewal and resistance to pegIFNα in JAK2-V617F-positive myeloproliferative neoplasms.
  5. Isolation of Murine Neonatal and Adult Osteomacs to Examine Their Role in the Hematopoietic Niche.
  6. Degradation meets development: Implications in β-cell development and diabetes.
  7. Combining Cell-Intrinsic and -Extrinsic Resistance to HIV-1 By Engineering Hematopoietic Stem Cells for CCR5 Knockout and B Cell Secretion of Therapeutic Antibodies.
  8. A fast-acting lipid checkpoint in G1 prevents mitotic defects.
  9. Autophagy regulates the maturation of hematopoietic precursors in the embryo.
  10. An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors.
  11. Ubiquitin-specific proximity labeling for the identification of E3 ligase substrates.
  12. HSPA9/mortalin inhibition disrupts erythroid maturation through a TP53-dependent mechanism in human CD34+ hematopoietic progenitor cells.
  13. Differential in vivo roles of Mpl cytoplasmic tyrosine residues in murine hematopoiesis and myeloproliferative disease.
  14. Bone marrow inflammation in haematological malignancies.
  15. Resilient anatomy and local plasticity of naive and stress haematopoiesis.
  16. The TLK-ASF1 histone chaperone pathway plays a critical role in IL-1b-mediated AML progression.
  1. Nat Commun. 2024 Mar 18. 15(1): 2428
    Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes.
    Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Feiyang Ma, Kelly Chien, Monica Del Rey, Sanam Loghavi, Guillermo Montalban-Bravo, Vera Adema, Bethany Wildeman, Rashmi Kanagal-Shamanna, Alexandre Bazinet, Helen T Chifotides, Natthakan Thongon, Xavier Calvo, Jesús María Hernández-Rivas, Maria Díez-Campelo, Guillermo Garcia-Manero, Simona Colla.
      The molecular mechanisms of venetoclax-based therapy failure in patients with acute myeloid leukemia were recently clarified, but the mechanisms by which patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show an expansion of MDS hematopoietic stem cells (HSCs) with a granulo-monocytic-biased transcriptional differentiation state in MDS patients who initially responded to venetoclax but eventually relapsed. While MDS HSCs in an undifferentiated cellular state are sensitive to venetoclax treatment, differentiation towards a granulo-monocytic-biased transcriptional state, through the acquisition or expansion of clones with STAG2 or RUNX1 mutations, affects HSCs' survival dependence from BCL2-mediated anti-apoptotic pathways to TNFα-induced pro-survival NF-κB signaling and drives resistance to venetoclax-mediated cytotoxicity. Our findings reveal how hematopoietic stem and progenitor cell (HSPC) can eventually overcome therapy-induced depletion and underscore the importance of using close molecular monitoring to prevent HSPC hierarchical change in MDS patients enrolled in clinical trials of venetoclax.
    DOI:  https://doi.org/10.1038/s41467-024-46424-3
  2. Exp Hematol. 2024 Mar 15. pii: S0301-472X(24)00050-X. [Epub ahead of print] 104191
    Abcb10 regulates murine hematopoietic stem cell potential and erythroid differentiation.
    Ayano Yahagi, Makiko Mochizuki-Kashio, Yuriko Sorimachi, Keiyo Takubo, Ayako Nakamura-Ishizu.
      Erythropoiesis in the adult bone marrow (BM) relies on mitochondrial membrane transporters to facilitate heme and hemoglobin production. Erythrocytes in the bone marrow are produced though the differentiation of erythroid progenitor cells which originate from hematopoietic stem cells (HSCs). Whether and how mitochondria transporters potentiate HSCs and affect their differentiation towards erythroid lineage remains unclear. Here we show that the ATP-binding cassette (ABC) transporter 10 (Abcb10), located on the inner mitochondrial membrane, is essential for HSC maintenance and erythroid lineage differentiation. Induced deletion of Abcb10 in adult mice significantly increased erythroid progenitor cell and decreased HSC number within the BM. Functionally, Abcb10-deficient HSCs exhibited significant decrease in stem cell potential but with a skew towards erythroid-lineage differentiation. Mechanistically, deletion of Abcb10 rendered HSCs with excess mitochondrial iron accumulation and oxidative stress yet without alteration in mitochondrial bioenergetic function. However, impaired hematopoiesis could not be rescued through the in vivo administration of a mitochondrial iron chelator or antioxidant to Abcb10-deficient mice. Abcb10-mediated mitochondrial iron transfer is thus pivotal for the regulation of physiological HSC stem cell potential and erythroid lineage differentiation.
    Keywords:  ATP binding transporters; Hematopoietic stem cell; erythropoiesis; iron; mitochondria; quiescence
    DOI:  https://doi.org/10.1016/j.exphem.2024.104191
  3. Cytotherapy. 2024 Feb 24. pii: S1465-3249(24)00058-6. [Epub ahead of print]
    Ex vivo culture resting time impacts transplantation outcomes of genome-edited human hematopoietic stem and progenitor cells in xenograft mouse models.
    Selami Demirci, Muhammad B N Khan, Gabriela Hinojosa, Anh Le, Alexis Leonard, Khaled Essawi, Bjorg Gudmundsdottir, Xiong Liu, Jing Zeng, Zaina Inam, Rebecca Chu, Naoya Uchida, Daisuke Araki, Evan London, Henna Butt, Stacy A Maitland, Daniel E Bauer, Scot A Wolfe, Andre Larochelle, John F Tisdale.
      Ex vivo resting culture is a standard procedure following genome editing in hematopoietic stem and progenitor cells (HSPCs). However, prolonged culture may critically affect cell viability and stem cell function. We investigated whether varying durations of culture resting times impact the engraftment efficiency of human CD34+ HSPCs edited at the BCL11A enhancer, a key regulator in the expression of fetal hemoglobin. We employed electroporation to introduce CRISPR-Cas9 components for BCL11A enhancer editing and compared outcomes with nonelectroporated (NEP) and electroporated-only (EP) control groups. Post-electroporation, we monitored cell viability, death rates, and the frequency of enriched hematopoietic stem cell (HSC) fractions (CD34+CD90+CD45RA- cells) over a 48-hour period. Our findings reveal that while the NEP group showed an increase in cell numbers 24 hours post-electroporation, both EP and BCL11A-edited groups experienced significant cell loss. Although CD34+ cell frequency remained high in all groups for up to 48 hours post-electroporation, the frequency of the HSC-enriched fraction was significantly lower in the EP and edited groups compared to the NEP group. In NBSGW xenograft mouse models, both conditioned with busulfan and nonconditioned, we found that immediate transplantation post-electroporation led to enhanced engraftment without compromising editing efficiency. Human glycophorin A+ (GPA+) red blood cells (RBCs) sorted from bone marrow of all BCL11A edited mice exhibited similar levels of γ-globin expression, regardless of infusion time. Our findings underscore the critical importance of optimizing the culture duration between genome editing and transplantation. Minimizing this interval may significantly enhance engraftment success and minimize cell loss without compromising editing efficiency. These insights offer a pathway to improve the success rates of genome editing in HSPCs, particularly for conditions like sickle cell disease.
    Keywords:  CRISPR-Cas9; engraftment; fetal hemoglobin; gene editing; hematopoiesis; sickle cell disease
    DOI:  https://doi.org/10.1016/j.jcyt.2024.02.011
  4. Blood. 2024 Mar 17. pii: blood.2023020270. [Epub ahead of print]
    Loss of Dnmt3a increased self-renewal and resistance to pegIFNα in JAK2-V617F-positive myeloproliferative neoplasms.
    Marc Usart, Jan Stetka, Damien Luque Paz, Nils Hansen, Quentin Kimmerlin, Tiago Almeida Fonseca, Melissa Lock, Lucia Kubovcakova, Riikka Karjalainen, Hui Hao-Shen, Anastasiya Börsch, Athimed El Taher, Jessica Schulz, Jean-Christophe Leroux, Stefan Dirnhofer, Radek C Skoda.
      Pegylated interferon alpha (pegIFNα) can induce molecular remissions in JAK2-V617F-positive myeloproliferative neoplasms (MPN) patients by targeting long-term hematopoietic stem cells (LT-HSCs). Additional somatic mutations in genes regulating LT-HSC self-renewal, such as DNMT3A, have been reported to have poorer responses to pegIFNα. We investigated if DNMT3A loss leads to alterations in JAK2-V617F LT-HSCs functions conferring resistance to pegIFNα treatment in a mouse model of MPN and in hematopoietic progenitors from MPN patients. Long-term treatment with pegIFNα normalized blood parameters, reduced splenomegaly and JAK2-V617F-chimerism in single-mutant JAK2-V617F (VF) mice. However, pegIFNα in VF;Dnmt3aΔ/Δ (VF;DmΔ/Δ) mice worsened splenomegaly and failed to reduce JAK2-V617F-chimerism. Furthermore, LT-HSCs from VF;DmΔ/Δ mice compared to VF were less prone to accumulate DNA damage and exit dormancy upon pegIFNα treatment. RNA-sequencing showed that IFNα induced stronger upregulation of inflammatory pathways in LT-HSCs from VF;DmΔ/Δ compared to VF mice, indicating that the resistance of VF;DmΔ/Δ LT-HSC was not due to failure in IFNα signaling. Transplantations of bone marrow from pegIFNα treated VF;DmΔ/Δ mice gave rise to more aggressive disease in secondary and tertiary recipients. Liquid cultures of hematopoietic progenitors from MPN patients with JAK2-V617F and DNMT3A mutation showed increased percentages of JAK2-V617F-positive colonies upon IFNα exposure, whereas in patients with JAK2-V617F alone the percentages of JAK2-V617F-positive colonies decreased or remained unchanged. PegIFNα combined with 5-azacytidine only partially overcame resistance in VF;DmΔ/Δ mice. However, this combination strongly decreased the JAK2-mutant allele burden in mice carrying VF mutation only, showing potential to inflict substantial damage preferentially to the JAK2-mutant clone.
    DOI:  https://doi.org/10.1182/blood.2023020270
  5. Methods Mol Biol. 2024 Mar 21.
    Isolation of Murine Neonatal and Adult Osteomacs to Examine Their Role in the Hematopoietic Niche.
    Safa F Mohamad, Melissa A Kacena.
      Maintenance of hematopoietic stem cell (HSC) function is an orchestrated event between multiple cell types, and crosstalk between these cell types is an essential part of HSC regulation. Among the cell groups of the niche involved in this process are a group of bone-resident macrophages known as osteomacs (OM). Previously, it was demonstrated that OM and osteoblasts contained within neonatal calvarial cells are critical to maintain hematopoietic function. Additionally, interactions between neonatal calvarial cells and megakaryocytes further enhance this hematopoietic activity. In this chapter, we explore one such interaction involving OM and osteoblasts in the hematopoietic niche. We describe a protocol to isolate OM from both neonatal and adult mice, and subsequently use colony-forming assays to demonstrate their interaction with osteoblasts in maintaining HSC function.
    Keywords:  Colony-forming assays; Hematopoietic niche; Macrophages; Osteoblasts; Osteomacs
    DOI:  https://doi.org/10.1007/7651_2024_535
  6. Cell Biol Int. 2024 Mar 18.
    Degradation meets development: Implications in β-cell development and diabetes.
    Akshaya Ashok, Guruprasad Kalthur, Anujith Kumar.
      Pancreatic development is orchestrated by timely synthesis and degradation of stage-specific transcription factors (TFs). The transition from one stage to another stage is dependent on the precise expression of the developmentally relevant TFs. Persistent expression of particular TF would impede the exit from the progenitor stage to the matured cell type. Intracellular protein degradation-mediated protein turnover contributes to a major extent to the turnover of these TFs and thereby dictates the development of different tissues. Since even subtle changes in the crucial cellular pathways would dramatically impact pancreatic β-cell performance, it is generally acknowledged that the biological activity of these pathways is tightly regulated by protein synthesis and degradation process. Intracellular protein degradation is executed majorly by the ubiquitin proteasome system (UPS) and Lysosomal degradation pathway. As more than 90% of the TFs are targeted to proteasomal degradation, this review aims to examine the crucial role of UPS in normal pancreatic β-cell development and how dysfunction of these pathways manifests in metabolic syndromes such as diabetes. Such understanding would facilitate designing a faithful approach to obtain a therapeutic quality of β-cells from stem cells.
    Keywords:  diabetes; pancreatic β-cells; stem cells; ubiquitin proteasome system; β-cell development
    DOI:  https://doi.org/10.1002/cbin.12155
  7. bioRxiv. 2024 Mar 09. pii: 2024.03.08.583956. [Epub ahead of print]
    Combining Cell-Intrinsic and -Extrinsic Resistance to HIV-1 By Engineering Hematopoietic Stem Cells for CCR5 Knockout and B Cell Secretion of Therapeutic Antibodies.
    William N Feist, Sofia E Luna, Kaya Ben-Efraim, Maria V Filsinger Interrante, Nelson A Amorin, Nicole M Johnston, Theodora U J Bruun, Hana Y Ghanim, Benjamin J Lesch, Amanda M Dudek, Matthew H Porteus.
      Autologous transplantation of CCR5 null hematopoietic stem and progenitor cells (HSPCs) is the only known cure for HIV-1 infection. However, this treatment is limited because of the rarity of CCR5 -null matched donors, the morbidities associated with allogeneic transplantation, and the prevalence of HIV-1 strains resistant to CCR5 knockout (KO) alone. Here, we propose a one-time therapy through autologous transplantation of HSPCs genetically engineered ex vivo to produce both CCR5 KO cells and long-term secretion of potent HIV-1 inhibiting antibodies from B cell progeny. CRISPR-Cas9-engineered HSPCs maintain engraftment capacity and multi-lineage potential in vivo and can be engineered to express multiple antibodies simultaneously. Human B cells engineered to express each antibody secrete neutralizing concentrations capable of inhibiting HIV-1 pseudovirus infection in vitro . This work lays the groundwork for a potential one-time functional cure for HIV-1 through combining the long-term delivery of therapeutic antibodies against HIV-1 and the known efficacy of CCR5 KO HSPC transplantation.
    DOI:  https://doi.org/10.1101/2024.03.08.583956
  8. Nat Commun. 2024 Mar 18. 15(1): 2441
    A fast-acting lipid checkpoint in G1 prevents mitotic defects.
    Marielle S Köberlin, Yilin Fan, Chad Liu, Mingyu Chung, Antonio F M Pinto, Peter K Jackson, Alan Saghatelian, Tobias Meyer.
      Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis.
    DOI:  https://doi.org/10.1038/s41467-024-46696-9
  9. Nat Commun. 2024 Mar 15. 15(1): 2255
    Autophagy regulates the maturation of hematopoietic precursors in the embryo.
    Yumin Liu, Linjuan Shi, Yifan Chen, Sifan Luo, Yuehang Chen, Hongtian Chen, Wenlang Lan, Xun Lu, Zhan Cao, Zehua Ye, Jinping Li, Bo Yu, Elaine Dzierzak, Zhuan Li.
      An understanding of the mechanisms regulating embryonic hematopoietic stem cell (HSC) development would facilitate their regeneration. The aorta-gonad-mesonephros region is the site for HSC production from hemogenic endothelial cells (HEC). While several distinct regulators are involved in this process, it is not yet known whether macroautophagy (autophagy) plays a role in hematopoiesis in the pre-liver stage. Here, we show that different states of autophagy exist in hematopoietic precursors and correlate with hematopoietic potential based on the LC3-RFP-EGFP mouse model. Deficiency of autophagy-related gene 5 (Atg5) specifically in endothelial cells disrupts endothelial to hematopoietic transition (EHT), by blocking the autophagic process. Using combined approaches, including single-cell RNA-sequencing (scRNA-seq), we have confirmed that Atg5 deletion interrupts developmental temporal order of EHT to further affect the pre-HSC I maturation, and that autophagy influences hemogenic potential of HEC and the formation of pre-HSC I likely via the nucleolin pathway. These findings demonstrate a role for autophagy in the formation/maturation of hematopoietic precursors.
    DOI:  https://doi.org/10.1038/s41467-024-46453-y
  10. Nat Immunol. 2024 Mar 21.
    An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors.
    Xuan Zhang, Baobao Song, Maximillian J Carlino, Guangyuan Li, Kyle Ferchen, Mi Chen, Evrett N Thompson, Bailee N Kain, Dan Schnell, Kairavee Thakkar, Michal Kouril, Kang Jin, Stuart B Hay, Sidharth Sen, David Bernardicius, Siyuan Ma, Sierra N Bennett, Josh Croteau, Ornella Salvatori, Melvin H Lye, Austin E Gillen, Craig T Jordan, Harinder Singh, Diane S Krause, Nathan Salomonis, H Leighton Grimes.
      Analysis of the human hematopoietic progenitor compartment is being transformed by single-cell multimodal approaches. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) enables coupled surface protein and transcriptome profiling, thereby revealing genomic programs underlying progenitor states. To perform CITE-seq systematically on primary human bone marrow cells, we used titrations with 266 CITE-seq antibodies (antibody-derived tags) and machine learning to optimize a panel of 132 antibodies. Multimodal analysis resolved >80 stem, progenitor, immune, stromal and transitional cells defined by distinctive surface markers and transcriptomes. This dataset enables flow cytometry solutions for in silico-predicted cell states and identifies dozens of cell surface markers consistently detected across donors spanning race and sex. Finally, aligning annotations from this atlas, we nominate normal marrow equivalents for acute myeloid leukemia stem cell populations that differ in clinical response. This atlas serves as an advanced digital resource for hematopoietic progenitor analyses in human health and disease.
    DOI:  https://doi.org/10.1038/s41590-024-01782-4
  11. Nat Chem Biol. 2024 Mar 21.
    Ubiquitin-specific proximity labeling for the identification of E3 ligase substrates.
    Hai-Tsang Huang, Ryan J Lumpkin, Ryan W Tsai, Shuyao Su, Xu Zhao, Yuan Xiong, James Chen, Nada Mageed, Katherine A Donovan, Eric S Fischer, William R Sellers.
      Protein ubiquitylation controls diverse processes within eukaryotic cells, including protein degradation, and is often dysregulated in disease. Moreover, small-molecule degraders that redirect ubiquitylation activities toward disease targets are an emerging and promising therapeutic class. Over 600 E3 ubiquitin ligases are expressed in humans, but their substrates remain largely elusive, necessitating the development of new methods for their discovery. Here we report the development of E3-substrate tagging by ubiquitin biotinylation (E-STUB), a ubiquitin-specific proximity labeling method that biotinylates ubiquitylated substrates in proximity to an E3 ligase of interest. E-STUB accurately identifies the direct ubiquitylated targets of protein degraders, including collateral targets and ubiquitylation events that do not lead to substrate degradation. It also detects known substrates of E3 ligase CRBN and VHL with high specificity. With the ability to elucidate proximal ubiquitylation events, E-STUB may facilitate the development of proximity-inducing therapeutics and act as a generalizable method for E3-substrate mapping.
    DOI:  https://doi.org/10.1038/s41589-024-01590-9
  12. Cell Stress Chaperones. 2024 Mar 18. pii: S1355-8145(24)00058-0. [Epub ahead of print]
    HSPA9/mortalin inhibition disrupts erythroid maturation through a TP53-dependent mechanism in human CD34+ hematopoietic progenitor cells.
    Christopher Butler, Morgan Dunmire, Jaebok Choi, Gabor Szalai, Anissa Johnson, Wei Lei, Xin Chen, Liang Liu, Wei Li, Matthew J Walter, Tuoen Liu.
      Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies characterized by abnormal hematopoietic cell maturation, increased apoptosis of bone marrow cells, and anemia. They are the most common myeloid blood cancers in American adults. The full complement of gene mutations that contribute to the phenotypes or clinical symptoms in MDS is not fully understood. Around 10%-25% of MDS patients harbor an interstitial heterozygous deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes, including HSPA9. The HSPA9 gene encodes for the protein mortalin, a highly conserved heat shock protein predominantly localized in mitochondria. Our prior study showed that knockdown of HSPA9 induces TP53-dependent apoptosis in human CD34+ hematopoietic progenitor cells. In this study, we explored the role of HSPA9 in regulating erythroid maturation using human CD34+ cells. We inhibited the expression of HSPA9 using gene knockdown and pharmacological inhibition, and found that inhibition of HSPA9 disrupted erythroid maturation as well as increased expression of p53 in CD34+ cells. To test whether the molecular mechanism of HSPA9 regulating erythroid maturation is TP53-dependent, we knocked-down HSPA9 and TP53 individually or in combination in human CD34+ cells. We found that knock-down of TP53 partially rescued the erythroid maturation defect induced by HSPA9 knock-down, suggesting that the defect in cells with reduced HSPA9 expression is TP53-dependent. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to the anemia observed in del(5q)-associated MDS patients due to the activation of TP53. SIGNIFICANCE STATEMENT: MDS is the most common adult myeloid blood cancer in the United States. A typical symptom of MDS patients includes fatigue that is associated with anemia. Some MDS patients harbor del(5q), with haploinsufficiency for a set of genes including HSPA9. We showed that inhibition of HSPA9 disrupts erythroid maturation in human CD34+ hematopoietic progenitor cells, through a TP53-dependent mechanism. Our findings not only indicate that reduced levels of HSPA9 may contribute to anemia observed in del(5q)-associated MDS patients, but also provide new insights into potential mechanisms of anemia.
    Keywords:  HSPA9/mortalin; TP53/p53; del(5q); erythroid maturation; myelodysplastic syndrome
    DOI:  https://doi.org/10.1016/j.cstres.2024.03.006
  13. Leukemia. 2024 Mar 15.
    Differential in vivo roles of Mpl cytoplasmic tyrosine residues in murine hematopoiesis and myeloproliferative disease.
    Kira Behrens, Maria Kauppi, Elizabeth M Viney, Andrew J Kueh, Craig D Hyland, Tracy A Willson, Liam Salleh, Carolyn A de Graaf, Jeffrey J Babon, Marco J Herold, Nicos A Nicola, Warren S Alexander.
      Thrombopoietin (Tpo), which binds to its specific receptor, the Mpl protein, is the major cytokine regulator of megakaryopoiesis and circulating platelet number. Tpo binding to Mpl triggers activation of Janus kinase 2 (Jak2) and phosphorylation of the receptor, as well as activation of several intracellular signalling cascades that mediate cellular responses. Three tyrosine (Y) residues in the C-terminal region of the Mpl intracellular domain have been implicated as sites of phosphorylation required for regulation of major Tpo-stimulated signalling pathways: Mpl-Y565, Mpl-Y599 and Mpl-Y604. Here, we have introduced mutations in the mouse germline and report a consistent physiological requirement for Mpl-Y599, mutation of which resulted in thrombocytopenia, deficient megakaryopoiesis, low hematopoietic stem cell (HSC) number and function, and attenuated responses to myelosuppression. We further show that in models of myeloproliferative neoplasms (MPN), where Mpl is required for pathogenesis, thrombocytosis was dependent on intact Mpl-Y599. In contrast, Mpl-Y565 was required for negative regulation of Tpo responses; mutation of this residue resulted in excess megakaryopoiesis at steady-state and in response to myelosuppression, and exacerbated thrombocytosis associated with MPN.
    DOI:  https://doi.org/10.1038/s41375-024-02219-5
  14. Nat Rev Immunol. 2024 Mar 15.
    Bone marrow inflammation in haematological malignancies.
    Madelon M E de Jong, Lanpeng Chen, Marc H G P Raaijmakers, Tom Cupedo.
      Tissue inflammation is a hallmark of tumour microenvironments. In the bone marrow, tumour-associated inflammation impacts normal niches for haematopoietic progenitor cells and mature immune cells and supports the outgrowth and survival of malignant cells residing in these niche compartments. This Review provides an overview of our current understanding of inflammatory changes in the bone marrow microenvironment of myeloid and lymphoid malignancies, using acute myeloid leukaemia and multiple myeloma as examples and highlights unique and shared features of inflammation in niches for progenitor cells and plasma cells. Importantly, inflammation exerts profoundly different effects on normal bone marrow niches in these malignancies, and we provide context for possible drivers of these divergent effects. We explore the role of tumour cells in inflammatory changes, as well as the role of cellular constituents of normal bone marrow niches, including myeloid cells and stromal cells. Integrating knowledge of disease-specific dynamics of malignancy-associated bone marrow inflammation will provide a necessary framework for future targeting of these processes to improve patient outcome.
    DOI:  https://doi.org/10.1038/s41577-024-01003-x
  15. Nature. 2024 Mar 20.
    Resilient anatomy and local plasticity of naive and stress haematopoiesis.
    Qingqing Wu, Jizhou Zhang, Sumit Kumar, Siyu Shen, Morgan Kincaid, Courtney B Johnson, Yanan Sophia Zhang, Raphaël Turcotte, Clemens Alt, Kyoko Ito, Shelli Homan, Bryan E Sherman, Tzu-Yu Shao, Anastasiya Slaughter, Benjamin Weinhaus, Baobao Song, Marie Dominique Filippi, H Leighton Grimes, Charles P Lin, Keisuke Ito, Sing Sing Way, J Matthew Kofron, Daniel Lucas.
      The bone marrow adjusts blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses are unknown owing to the lack of methods to visualize most steps of blood production. Here we develop strategies to image multipotent haematopoiesis, erythropoiesis and lymphopoiesis in mice. We combine these with imaging of myelopoiesis1 to define the anatomy of normal and stress haematopoiesis. In the steady state, across the skeleton, single stem cells and multipotent progenitors distribute through the marrow enriched near megakaryocytes. Lineage-committed progenitors are recruited to blood vessels, where they contribute to lineage-specific microanatomical structures composed of progenitors and immature cells, which function as the production sites for each major blood lineage. This overall anatomy is resilient to insults, as it was maintained after haemorrhage, systemic bacterial infection and granulocyte colony-stimulating factor (G-CSF) treatment, and during ageing. Production sites enable haematopoietic plasticity as they differentially and selectively modulate their numbers and output in response to insults. We found that stress responses are variable across the skeleton: the tibia and the sternum respond in opposite ways to G-CSF, and the skull does not increase erythropoiesis after haemorrhage. Our studies enable in situ analyses of haematopoiesis, define the anatomy of normal and stress responses, identify discrete microanatomical production sites that confer plasticity to haematopoiesis, and uncover unprecedented heterogeneity of stress responses across the skeleton.
    DOI:  https://doi.org/10.1038/s41586-024-07186-6
  16. Blood. 2024 Mar 18. pii: blood.2023022079. [Epub ahead of print]
    The TLK-ASF1 histone chaperone pathway plays a critical role in IL-1b-mediated AML progression.
    Hsin-Yun Lin, Mona M Hosseini, John McClatchy, Marina Villamor-Payà, Sophia Jeng, Daniel Bottomly, Chia-Feng Tsai, Camilo Posso, Jeremy Jacobson, Andrew C Adey, Sara J C Gosline, Tao Liu, Shannon K McWeeney, Travis H Stracker, Anupriya Agarwal.
      Identifying and targeting microenvironment-driven pathways that are active across acute myeloid leukemia (AML) genetic subtypes should allow the development of more broadly effective therapies. The pro-inflammatory cytokine IL-1 is abundant in the AML microenvironment and promotes leukemic growth. Through RNA-sequencing analysis, we identify that IL-1 upregulated ASF1B (anti-silencing function-1B), a histone chaperone, in AML progenitors compared to healthy progenitors. ASF1B, along with its paralogous protein ASF1A recruits H3-H4 histones onto the replication fork during S-phase, a process regulated by tousled-like kinase 1 and 2 (TLKs). While ASF1s and TLKs are known to be overexpressed in multiple solid tumors and associated with poor prognosis, their functional roles in hematopoiesis and inflammation-driven leukemia remain unexplored. In this study, we identify that ASF1s and TLKs are over-expressed in multiple genetic subtypes of AML. We demonstrate that depletion of ASF1s significantly reduces leukemic cell growth in both in vitro and in vivo models using human cells. Using a murine model we show that overexpression of ASF1B accelerates leukemia progression. Moreover, Asf1b or Tlk2 deletion delayed leukemia progression while these proteins are dispensable for normal hematopoiesis. Through proteomics and phosphoproteomics analyses, we uncover that the TLK-ASF1 pathway promotes leukemogenesis by impacting the cell cycle and DNA damage pathways. Collectively, our findings identify the TLK1-ASF1 pathway as a novel mediator of inflammatory signaling and a promising therapeutic target for AML treatment across diverse genetic subtypes. Selective inhibition of this pathway offers potential opportunities to intervene effectively, address intratumoral heterogeneity, and ultimately improve clinical outcomes in AML.
    DOI:  https://doi.org/10.1182/blood.2023022079
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