{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:52:49Z","timestamp":1791363169724,"version":"4.3.1"},"reference-count":50,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,12,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A common feature of both congenital and acquired forms of bone marrow failure is an increased risk of developing acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Indeed, the development of MDS or AML is now the major cause of mortality in patients with congenital neutropenia. Thus, there is a pressing clinical need to develop better strategies to prevent, diagnose early, and treat MDS\/AML in patients with congenital neutropenia and other bone marrow failure syndromes. Here, we discuss recent data characterizing clonal hematopoiesis and progression to myeloid malignancy in congenital neutropenia, focusing on severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome. We summarize recent studies showing excellent outcomes after allogenic hematopoietic stem cell transplantation for many (but not all) patients with congenital neutropenia, including patients with SCN with active myeloid malignancy who underwent transplantation. Finally, we discuss how these new data inform the current clinical management of patients with congenital neutropenia.<\/jats:p>","DOI":"10.1182\/hematology.2021000286","type":"journal-article","created":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T07:17:39Z","timestamp":1639120659000},"page":"514-520","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":8,"title":["Impaired myelopoiesis in congenital neutropenia: insights into clonal and malignant hematopoiesis"],"prefix":"10.1182","volume":"2021","author":[{"given":"Julia T.","family":"Warren","sequence":"first","affiliation":[{"name":"Division of Hematology-Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"Link","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2021,12,10]]},"reference":[{"key":"2021121012081653400_hem2021000286C1","doi-asserted-by":"crossref","first-page":"17032","DOI":"10.1038\/nrdp.2017.32","article-title":"Severe congenital neutropenias","volume":"3","author":"Skokowa","year":"2017","journal-title":"Nat Rev Dis Primers"},{"issue":"1","key":"2021121012081653400_hem2021000286C2","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1056\/NEJMoa0805051","article-title":"A syndrome with congenital neutropenia and mutations in G6PC3","volume":"360","author":"Boztug","year":"2009","journal-title":"N Engl J Med"},{"issue":"4","key":"2021121012081653400_hem2021000286C3","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/70544","article-title":"Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis","volume":"23","author":"Horwitz","year":"1999","journal-title":"Nat Genet"},{"issue":"1","key":"2021121012081653400_hem2021000286C4","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/ng1940","article-title":"HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease)","volume":"39","author":"Klein","year":"2007","journal-title":"Nat Genet"},{"issue":"4","key":"2021121012081653400_hem2021000286C5","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/j.1365-2141.2009.07888.x","article-title":"Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia","volume":"147","author":"Xia","year":"2009","journal-title":"Br J Haematol"},{"issue":"10","key":"2021121012081653400_hem2021000286C6","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1182\/blood.V81.10.2496.2496","article-title":"A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia","volume":"81","author":"Dale","year":"1993","journal-title":"Blood"},{"issue":"2","key":"2021121012081653400_hem2021000286C7","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1111\/j.1365-2141.2010.08216.x","article-title":"Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy","volume":"150","author":"Rosenberg","year":"2010","journal-title":"Br J Haematol"},{"issue":"1","key":"2021121012081653400_hem2021000286C8","first-page":"45","article-title":"Analysis of risk factors for myelodysplasias, leukemias and death from infection among patients with congenital neutropenia. Experience of the French Severe Chronic Neutropenia Study Group","volume":"90","author":"Donadieu","year":"2005","journal-title":"Haematologica"},{"issue":"3","key":"2021121012081653400_hem2021000286C9","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1002\/ajh.25374","article-title":"Neutropenia in the age of genetic testing: advances and challenges","volume":"94","author":"Furutani","year":"2019","journal-title":"Am J Hematol"},{"issue":"22","key":"2021121012081653400_hem2021000286C10","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1056\/NEJMoa1301689","article-title":"Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia","volume":"368","author":"Ley","year":"2013","journal-title":"N Engl J Med"},{"issue":"14","key":"2021121012081653400_hem2021000286C11","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1182\/blood-2013-11-538025","article-title":"Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis","volume":"123","author":"Skokowa","year":"2014","journal-title":"Blood"},{"issue":"2","key":"2021121012081653400_hem2021000286C12","first-page":"429","article-title":"Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy","volume":"96","author":"Freedman","year":"2000","journal-title":"Blood"},{"issue":"12","key":"2021121012081653400_hem2021000286C13","doi-asserted-by":"crossref","first-page":"4579","DOI":"10.1182\/blood.V86.12.4579.bloodjournal86124579","article-title":"Monosomy 7 and activating RAS mutations accompany malignant transformation in patients with congenital neutropenia","volume":"86","author":"Kalra","year":"1995","journal-title":"Blood"},{"issue":"5","key":"2021121012081653400_hem2021000286C14","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1182\/blood-2007-03-081216","article-title":"Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia","volume":"110","author":"Link","year":"2007","journal-title":"Blood"},{"issue":"2","key":"2021121012081653400_hem2021000286C15","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.hoc.2009.01.007","article-title":"Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment","volume":"23","author":"Burroughs","year":"2009","journal-title":"Hematol Oncol Clin North Am"},{"issue":"4","key":"2021121012081653400_hem2021000286C16","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1016\/j.jpeds.2013.11.039","article-title":"Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry","volume":"164","author":"Myers","year":"2014","journal-title":"J Pediatr"},{"issue":"3","key":"2021121012081653400_hem2021000286C17","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1053\/j.seminhematol.2006.04.006","article-title":"Shwachman-Diamond syndrome","volume":"43","author":"Shimamura","year":"2006","journal-title":"Semin Hematol"},{"issue":"5","key":"2021121012081653400_hem2021000286C18","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1111\/j.1399-0004.2010.01468.x","article-title":"Comparative analysis of Shwachman- Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation","volume":"79","author":"Hashmi","year":"2011","journal-title":"Clin Genet"},{"issue":"12","key":"2021121012081653400_hem2021000286C19","doi-asserted-by":"crossref","first-page":"4628","DOI":"10.1182\/blood-2005-11-4370","article-title":"The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy","volume":"107","author":"Rosenberg","year":"2006","journal-title":"Blood"},{"issue":"1","key":"2021121012081653400_hem2021000286C20","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1038\/s41467-021-21588-4","article-title":"Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman- Diamond syndrome","volume":"12","author":"Kennedy","year":"2021","journal-title":"Nat Commun"},{"issue":"6","key":"2021121012081653400_hem2021000286C21","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1056\/NEJMoa1611604","article-title":"Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation","volume":"376","author":"Lindsley","year":"2017","journal-title":"N Engl J Med"},{"issue":"26","key":"2021121012081653400_hem2021000286C22","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1056\/NEJMoa1409405","article-title":"Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence","volume":"371","author":"Genovese","year":"2014","journal-title":"N Engl J Med"},{"issue":"26","key":"2021121012081653400_hem2021000286C23","doi-asserted-by":"crossref","first-page":"2488","DOI":"10.1056\/NEJMoa1408617","article-title":"Age-related clonal hematopoiesis associated with adverse outcomes","volume":"371","author":"Jaiswal","year":"2014","journal-title":"N Engl J Med"},{"issue":"14","key":"2021121012081653400_hem2021000286C24","first-page":"1599","article-title":"Clonal hematopoiesis and risk for hematologic malignancy","volume":"136","author":"Warren","year":"2020","journal-title":"Blood"},{"issue":"4","key":"2021121012081653400_hem2021000286C25","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1182\/blood-2017-08-801985","article-title":"Somatic mutations and clonal hematopoiesis in congenital neutropenia","volume":"131","author":"Xia","year":"2018","journal-title":"Blood"},{"issue":"4","key":"2021121012081653400_hem2021000286C26","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1084\/jem.189.4.683","article-title":"Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia\/acute myeloid leukemia-derived mutation in the G- CSF receptor gene","volume":"189","author":"Hermans","year":"1999","journal-title":"J Exp Med"},{"issue":"1","key":"2021121012081653400_hem2021000286C27","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1182\/blood.V92.1.32.413k42_32_39","article-title":"Perturbed granulopoiesis in mice with a targeted mutation in the granulocyte colony-stimulating factor receptor gene associated with severe chronic neutropenia","volume":"92","author":"Hermans","year":"1998","journal-title":"Blood"},{"issue":"3","key":"2021121012081653400_hem2021000286C28","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1172\/JCI3216","article-title":"Increased granulocyte colony-stimulating factor responsiveness but normal resting granulopoiesis in mice carrying a targeted granulocyte colony-stimulating factor receptor mutation derived from a patient with severe congenital neutropenia","volume":"102","author":"McLemore","year":"1998","journal-title":"J Clin Invest"},{"issue":"3","key":"2021121012081653400_hem2021000286C29","first-page":"946","article-title":"Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5","volume":"118","author":"Liu","year":"2008","journal-title":"J Clin Invest"},{"issue":"14","key":"2021121012081653400_hem2021000286C30","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1182\/blood.2021010815","article-title":"Incidence and prognosis of clonal hematopoiesis in patients with chronic idiopathic neutropenia","volume":"138","author":"Tsaknakis","year":"2021","journal-title":"Blood"},{"issue":"4","key":"2021121012081653400_hem2021000286C31","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/ng1994","article-title":"The Shwachman-Bodian- Diamond syndrome protein mediates translational activation of ribosomes in yeast","volume":"39","author":"Menne","year":"2007","journal-title":"Nat Genet"},{"issue":"16","key":"2021121012081653400_hem2021000286C32","doi-asserted-by":"crossref","first-page":"4305","DOI":"10.1182\/blood-2011-06-353938","article-title":"Defective ribosome assembly in Shwachman-Diamond syndrome","volume":"118","author":"Wong","year":"2011","journal-title":"Blood"},{"issue":"10","key":"2021121012081653400_hem2021000286C33","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.3324\/haematol.2015.131573","article-title":"Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes","volume":"100","author":"Zambetti","year":"2015","journal-title":"Haematologica"},{"key":"2021121012081653400_hem2021000286C34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1182\/asheducation-2015.1.1","article-title":"Game of clones: the genomic evolution of severe congenital neutropenia","volume":"2015","author":"Touw","year":"2015","journal-title":"Hematol Am Soc Hematol Educ Program"},{"issue":"5","key":"2021121012081653400_hem2021000286C35","doi-asserted-by":"crossref","first-page":"906.e6","DOI":"10.1016\/j.stem.2021.03.023","article-title":"iPSC modeling of stage-specific leukemogenesis reveals BAALC as a key oncogene in severe congenital neutropenia","volume":"28","author":"Dannenmann","year":"2021","journal-title":"Cell Stem Cell"},{"issue":"8","key":"2021121012081653400_hem2021000286C36","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1038\/s41409-020-0800-1","article-title":"HSCT may lower leukemia risk in ELANE neutropenia: a before-after study from the French Severe Congenital Neutropenia Registry","volume":"55","author":"Rotulo","year":"2020","journal-title":"Bone Marrow Transplant"},{"issue":"22","key":"2021121012081653400_hem2021000286C37","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1182\/blood.V128.22.1326.1326","article-title":"Termination and frameshift mutations in ELANE are associated with adverse outcomes in patients with severe chronic neutropenia","volume":"128","author":"Dale","year":"2016","journal-title":"Blood"},{"issue":"1","key":"2021121012081653400_hem2021000286C38","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/MOH.0000000000000105","article-title":"The diversity of mutations and clinical outcomes for ELANE-associated neutropenia","volume":"22","author":"Makaryan","year":"2015","journal-title":"Curr Opin Hematol"},{"issue":"16","key":"2021121012081653400_hem2021000286C39","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1182\/blood-2015-02-628859","article-title":"Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation","volume":"126","author":"Fioredda","year":"2015","journal-title":"Blood"},{"issue":"21","key":"2021121012081653400_hem2021000286C40","doi-asserted-by":"crossref","first-page":"3347","DOI":"10.1182\/blood.V122.21.3347.3347","article-title":"Improved outcome of stem cell transplantation for severe chronic neutropenia with or without secondary leukemia: a long-term analysis of European data for more than 25 years by the SCNIR","volume":"122","author":"Zeidler","year":"2013","journal-title":"Blood"},{"issue":"9","key":"2021121012081653400_hem2021000286C41","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1038\/s41409-020-0863-z","article-title":"Long-term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT)","volume":"55","author":"Cesaro","year":"2020","journal-title":"Bone Marrow Transplant"},{"issue":"8","key":"2021121012081653400_hem2021000286C42","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1016\/j.bbmt.2020.04.029","article-title":"Hematopoietic stem cell transplantation for Shwachman-Diamond syndrome","volume":"26","author":"Myers","year":"2020","journal-title":"Biol Blood Marrow Transplant"},{"issue":"3","key":"2021121012081653400_hem2021000286C43","doi-asserted-by":"crossref","first-page":"e238","DOI":"10.1016\/S2352-3026(19)30206-6","article-title":"Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study","volume":"7","author":"Myers","year":"2020","journal-title":"Lancet Haematol"},{"issue":"2","key":"2021121012081653400_hem2021000286C44","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1002\/ajh.22242","article-title":"Congenital and acquired neutropenias consensus guidelines on therapy and follow-up in childhood from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica)","volume":"87","author":"Fioredda","year":"2012","journal-title":"Am J Hematol"},{"issue":"3","key":"2021121012081653400_hem2021000286C45","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1053\/j.seminhematol.2013.06.010","article-title":"Evaluation and management of patients with isolated neutropenia","volume":"50","author":"Newburger","year":"2013","journal-title":"Semin Hematol"},{"issue":"11","key":"2021121012081653400_hem2021000286C46","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.1158\/1078-0432.CCR-17-0428","article-title":"Recommendations for surveillance for children with leukemia-predisposing conditions","volume":"23","author":"Porter","year":"2017","journal-title":"Clin Cancer Res"},{"issue":"2","key":"2021121012081653400_hem2021000286C47","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/j.1365-2141.2009.07611.x","article-title":"The route to development of myelodysplastic syndrome\/acute myeloid leukaemia in Shwachman-Diamond syndrome: the role of ageing, karyotype instability, and acquired chromosome anomalies","volume":"145","author":"Maserati","year":"2009","journal-title":"Br J Haematol"},{"issue":"4","key":"2021121012081653400_hem2021000286C48","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/leu.2008.369","article-title":"The isochromosome i(7)(q10) carrying c.258\u200a+\u200a2t&gt;c mutation of the SBDS gene does not promote development of myeloid malignancies in patients with Shwachman syndrome","volume":"23","author":"Minelli","year":"2009","journal-title":"Leukemia"},{"issue":"4","key":"2021121012081653400_hem2021000286C49","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1111\/j.1365-2141.2012.09033.x","article-title":"Deletion of chromosome 20 in bone marrow of patients with Shwachman-Diamond syndrome, loss of the EIF6 gene and benign prognosis","volume":"157","author":"Pressato","year":"2012","journal-title":"Br J Haematol"},{"issue":"9","key":"2021121012081653400_hem2021000286C50","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.3324\/haematol.2011.057489","article-title":"Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome","volume":"97","author":"Donadieu","year":"2012","journal-title":"Haematologica"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2021\/1\/514\/1851470\/514warren.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2021\/1\/514\/1851470\/514warren.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T17:51:52Z","timestamp":1699897912000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2021\/1\/514\/482979\/Impaired-myelopoiesis-in-congenital-neutropenia"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,10]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12,10]]},"published-print":{"date-parts":[[2021,12,10]]}},"URL":"https:\/\/doi.org\/10.1182\/hematology.2021000286","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,12,10]]},"published":{"date-parts":[[2021,12,10]]}}}