Differential Transcriptional Control of Hematopoiesis in Congenital and Cyclic Neutropenia Patients Harboring Mutations

Overview

Journal Haematologica

Specialty Hematology

Date 2023 Oct 19

PMID 37855057

Authors

Alexander Zeidler

Natalia Borbaran-Bravo

Benjamin Dannenmann

Malte Ritter

Masoud Nasri

Maksim Klimiankou

Sergey Kandabarau

Azadeh Zahabi

Josef Konig

Cornelia Zeidler

Julia Skokowa

Karl Welte

Affiliations

Soon will be listed here.

Abstract

Mutations in the ELANE gene, encoding the neutrophil elastase (NE) protein, are responsible for most cyclic neutropenia (CyN) cases and approximately 25% of congenital neutropenia (CN) cases. In CN and in CyN, a median of 2.8% of CD34+ cells were early CD49f+ hematopoietic stem cells (eHSC) that did not express ELANE and thus escape from the unfolded protein response (UPR) caused by mutated NE. In CyN, the CD49f+ cells respond to granulocyte colony-stimulating factor (G-CSF) with a significant upregulation of the hematopoietic stem cell-specific transcription factors, C/EBPα, MLL1, HOXA9, MEIS1, and HLF during the ascending arm of the cycle, resulting in the differentiation of myeloid cells to mature neutrophils at the cycle peak. However, NE protein released by neutrophils at the cycle's peak caused a negative feedback loop on granulopoiesis through the proteolytic digestion of G-CSF. In contrast, in CN patients, CD49f+ cells failed to express mRNA levels of HSC-specific transcription factors mentioned above. Rescue of C/EBPα expression in CN restored granulopoiesis.

Citing Articles

De Novo Deep Intron ELANE Mutation Resulting in Severe Congenital Neutropenia.

Shu Z, Deng M, Han T, Mao H J Clin Immunol. 2024; 44(8):183.

PMID: 39172268 DOI: 10.1007/s10875-024-01783-w.

References

Argiropoulos B, Yung E, Humphries R . Unraveling the crucial roles of Meis1 in leukemogenesis and normal hematopoiesis. Genes Dev. 2007; 21(22):2845-9. DOI: 10.1101/gad.1619407. View

Li F, Horwitz M . Characterization of mutant neutrophil elastase in severe congenital neutropenia. J Biol Chem. 2001; 276(17):14230-41. DOI: 10.1074/jbc.M010279200. View

Fioredda F, Skokowa J, Tamary H, Spanoudakis M, Farruggia P, Almeida A . The European Guidelines on Diagnosis and Management of Neutropenia in Adults and Children: A Consensus Between the European Hematology Association and the EuNet-INNOCHRON COST Action. Hemasphere. 2023; 7(4):e872. PMC: 10065839. DOI: 10.1097/HS9.0000000000000872. View

Ye M, Zhang H, Amabile G, Yang H, Staber P, Zhang P . C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence. Nat Cell Biol. 2013; 15(4):385-94. PMC: 3781213. DOI: 10.1038/ncb2698. View

Bonilla M, Dale D, Zeidler C, Last L, Reiter A, Ruggeiro M . Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias. Br J Haematol. 1994; 88(4):723-30. DOI: 10.1111/j.1365-2141.1994.tb05110.x. View

Makaryan V, Zeidler C, Bolyard A, Skokowa J, Rodger E, Kelley M . The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol. 2014; 22(1):3-11. PMC: 4380169. DOI: 10.1097/MOH.0000000000000105. View

Avellino R, Mulet-Lazaro R, Havermans M, Hoogenboezem R, Smeenk L, Salomonis N . Induced cell-autonomous neutropenia systemically perturbs hematopoiesis in Cebpa enhancer-null mice. Blood Adv. 2021; 6(5):1406-1419. PMC: 8905702. DOI: 10.1182/bloodadvances.2021005851. View

Milne T, Briggs S, Brock H, Martin M, Gibbs D, Allis C . MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell. 2002; 10(5):1107-17. DOI: 10.1016/s1097-2765(02)00741-4. View

Lawrence H, Christensen J, Fong S, Hu Y, Weissman I, Sauvageau G . Loss of expression of the Hoxa-9 homeobox gene impairs the proliferation and repopulating ability of hematopoietic stem cells. Blood. 2005; 106(12):3988-94. PMC: 1895111. DOI: 10.1182/blood-2005-05-2003. View

10.

Belluschi S, Calderbank E, Ciaurro V, Pijuan-Sala B, Santoro A, Mende N . Myelo-lymphoid lineage restriction occurs in the human haematopoietic stem cell compartment before lymphoid-primed multipotent progenitors. Nat Commun. 2018; 9(1):4100. PMC: 6173731. DOI: 10.1038/s41467-018-06442-4. View

11.

Hasemann M, Lauridsen F, Waage J, Jakobsen J, Frank A, Schuster M . C/EBPα is required for long-term self-renewal and lineage priming of hematopoietic stem cells and for the maintenance of epigenetic configurations in multipotent progenitors. PLoS Genet. 2014; 10(1):e1004079. PMC: 3886906. DOI: 10.1371/journal.pgen.1004079. View

12.

Dannenmann B, Zahabi A, Mir P, Oswald B, Bernhard R, Klimiankou M . Human iPSC-based model of severe congenital neutropenia reveals elevated UPR and DNA damage in CD34 cells preceding leukemic transformation. Exp Hematol. 2019; 71:51-60. DOI: 10.1016/j.exphem.2018.12.006. View

13.

Skokowa J, Fobiwe J, Dan L, Thakur B, Welte K . Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1. Blood. 2009; 114(14):3044-51. DOI: 10.1182/blood-2008-11-188755. View

14.

Rosenberg P, Zeidler C, Bolyard A, Alter B, Bonilla M, Boxer L . Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br J Haematol. 2010; 150(2):196-9. PMC: 2906693. DOI: 10.1111/j.1365-2141.2010.08216.x. View

15.

Klimiankou M, Mellor-Heineke S, Klimenkova O, Reinel E, Uenalan M, Kandabarau S . Two cases of cyclic neutropenia with acquired CSF3R mutations, with 1 developing AML. Blood. 2016; 127(21):2638-41. DOI: 10.1182/blood-2015-12-685784. View

16.

Artinger E, Mishra B, Zaffuto K, Li B, Chung E, Moore A . An MLL-dependent network sustains hematopoiesis. Proc Natl Acad Sci U S A. 2013; 110(29):12000-5. PMC: 3718146. DOI: 10.1073/pnas.1301278110. View

17.

Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick J . Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011; 333(6039):218-21. DOI: 10.1126/science.1201219. View

18.

Huang Y, Sitwala K, Bronstein J, Sanders D, Dandekar M, Collins C . Identification and characterization of Hoxa9 binding sites in hematopoietic cells. Blood. 2011; 119(2):388-98. PMC: 3257007. DOI: 10.1182/blood-2011-03-341081. View

19.

Pineault N, Helgason C, Lawrence H, Humphries R . Differential expression of Hox, Meis1, and Pbx1 genes in primitive cells throughout murine hematopoietic ontogeny. Exp Hematol. 2002; 30(1):49-57. DOI: 10.1016/s0301-472x(01)00757-3. View

20.

Skokowa J, Cario G, Uenalan M, Schambach A, Germeshausen M, Battmer K . LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nat Med. 2006; 12(10):1191-7. DOI: 10.1038/nm1474. View