Skip to main content
Erschienen in:

16.08.2024 | Progress in Hematology

Molecular pathophysiology of germline mutations in acute myeloid leukemia

verfasst von: Yasunobu Nagata

Erschienen in: International Journal of Hematology | Ausgabe 4/2024

Einloggen, um Zugang zu erhalten

Abstract

Germline (GL) predisposition to acute myeloid leukemia (AML) has been established as an independent disease entity in the latest World Health Organization classification. Following the American College of Medical Genetics and Genomics guidelines, GL variants were interpreted as causal if they were classified as “pathogenic.” GL predisposition can be divided into three groups with different phenotypes, and play an important role in the pathogenesis of adult-onset AML. The clinical course and age of onset of myeloid neoplasms varied considerably for each gene. For example, patients with GATA2 GL variants develop AML before the age of 30 along with bone marrow failure, whereas those with DDX41 GL variants tend to develop AML after the age of 50 without any preceding hematological abnormalities or organ dysfunction. A comprehensive analysis of adult-onset myelodysplastic syndromes in transplant donors showed a 7% frequency of pathogenic GL variants, with DDX41 being the most frequent gene mutation at approximately 3.8%. Future research on GL predisposition at any age of myeloid neoplasm onset will assist in early and accurate diagnosis, development of effective treatment strategies, and selection of suitable donors for stem cell transplantation.
Literatur
1.
Zurück zum Zitat Porter CC. Germ line mutations associated with leukemias. Hematol Am Soc Hematol Educ Program. 2016;2016:302–8.CrossRef Porter CC. Germ line mutations associated with leukemias. Hematol Am Soc Hematol Educ Program. 2016;2016:302–8.CrossRef
2.
Zurück zum Zitat Yamaguchi H. Significance of gene diagnosis in acute myeloid leukemia with the emergence of new molecular target drug treatment. J Nippon Med Sch. 2022;89:470–8.PubMedCrossRef Yamaguchi H. Significance of gene diagnosis in acute myeloid leukemia with the emergence of new molecular target drug treatment. J Nippon Med Sch. 2022;89:470–8.PubMedCrossRef
3.
Zurück zum Zitat Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36:1703–19.PubMedPubMedCentralCrossRef Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36:1703–19.PubMedPubMedCentralCrossRef
4.
Zurück zum Zitat Klco JM, Mullighan CG. Advances in germline predisposition to acute leukaemias and myeloid neoplasms. Nat Rev Cancer. 2021;21:122–37.PubMedCrossRef Klco JM, Mullighan CG. Advances in germline predisposition to acute leukaemias and myeloid neoplasms. Nat Rev Cancer. 2021;21:122–37.PubMedCrossRef
5.
Zurück zum Zitat Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373:2336–46.PubMedPubMedCentralCrossRef Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373:2336–46.PubMedPubMedCentralCrossRef
6.
Zurück zum Zitat Schwartz JR, Ma J, Lamprecht T, Walsh M, Wang S, Bryant V, et al. The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun. 2017;8:1557.PubMedPubMedCentralCrossRef Schwartz JR, Ma J, Lamprecht T, Walsh M, Wang S, Bryant V, et al. The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun. 2017;8:1557.PubMedPubMedCentralCrossRef
7.
Zurück zum Zitat Keel SB, Scott A, Sanchez-Bonilla M, Ho PA, Gulsuner S, Pritchard CC, et al. Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients. Haematologica. 2016;101:1343–50.PubMedPubMedCentralCrossRef Keel SB, Scott A, Sanchez-Bonilla M, Ho PA, Gulsuner S, Pritchard CC, et al. Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients. Haematologica. 2016;101:1343–50.PubMedPubMedCentralCrossRef
8.
Zurück zum Zitat Feurstein S, Churpek JE, Walsh T, Keel S, Hakkarainen M, Schroeder T, et al. Germline variants drive myelodysplastic syndrome in young adults. Leukemia. 2021;35:2439–44.PubMedPubMedCentralCrossRef Feurstein S, Churpek JE, Walsh T, Keel S, Hakkarainen M, Schroeder T, et al. Germline variants drive myelodysplastic syndrome in young adults. Leukemia. 2021;35:2439–44.PubMedPubMedCentralCrossRef
9.
Zurück zum Zitat Feurstein S, Trottier AM, Estrada-Merly N, Pozsgai M, McNeely K, Drazer MW, et al. Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages. Blood. 2022;140:2533–48.PubMedPubMedCentralCrossRef Feurstein S, Trottier AM, Estrada-Merly N, Pozsgai M, McNeely K, Drazer MW, et al. Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages. Blood. 2022;140:2533–48.PubMedPubMedCentralCrossRef
10.
Zurück zum Zitat Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka H-M, et al. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140:1200–28.PubMedPubMedCentralCrossRef Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka H-M, et al. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140:1200–28.PubMedPubMedCentralCrossRef
11.
Zurück zum Zitat Bougeard G, Renaux-Petel M, Flaman J-M, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-fraumeni syndrome from tp53 mutation carriers. J Clin Oncol. 2015;33:2345–52.PubMedCrossRef Bougeard G, Renaux-Petel M, Flaman J-M, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-fraumeni syndrome from tp53 mutation carriers. J Clin Oncol. 2015;33:2345–52.PubMedCrossRef
12.
Zurück zum Zitat Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, et al. Beyond Li fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009;27:1250–6.PubMedCrossRef Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, et al. Beyond Li fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009;27:1250–6.PubMedCrossRef
13.
Zurück zum Zitat Duployez N, Largeaud L, Duchmann M, Kim R, Rieunier J, Lambert J, et al. Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study. Blood. 2022;140:756–68.PubMedPubMedCentralCrossRef Duployez N, Largeaud L, Duchmann M, Kim R, Rieunier J, Lambert J, et al. Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study. Blood. 2022;140:756–68.PubMedPubMedCentralCrossRef
14.
Zurück zum Zitat Homan CC, Drazer MW, Yu K, Lawrence DM, Feng J, Arriola-Martinez L, et al. Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41. Blood Adv. 2023;7:6092–107.PubMedPubMedCentralCrossRef Homan CC, Drazer MW, Yu K, Lawrence DM, Feng J, Arriola-Martinez L, et al. Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41. Blood Adv. 2023;7:6092–107.PubMedPubMedCentralCrossRef
15.
Zurück zum Zitat Makishima H, Saiki R, Nannya Y, Korotev S, Gurnari C, Takeda J, et al. Germ line DDX41 mutations define a unique subtype of myeloid neoplasms. Blood. 2023;141:534–49.PubMedCrossRef Makishima H, Saiki R, Nannya Y, Korotev S, Gurnari C, Takeda J, et al. Germ line DDX41 mutations define a unique subtype of myeloid neoplasms. Blood. 2023;141:534–49.PubMedCrossRef
16.
Zurück zum Zitat Cazzola M. Introduction to a review series on germ line predisposition to hematologic malignancies: time to consider germ line testing. Blood. 2023;141:1509–12.PubMedCrossRef Cazzola M. Introduction to a review series on germ line predisposition to hematologic malignancies: time to consider germ line testing. Blood. 2023;141:1509–12.PubMedCrossRef
17.
Zurück zum Zitat Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N, et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. 2015;27:658–70.PubMedPubMedCentralCrossRef Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N, et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. 2015;27:658–70.PubMedPubMedCentralCrossRef
19.
Zurück zum Zitat Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.PubMedPubMedCentralCrossRef Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.PubMedPubMedCentralCrossRef
20.
Zurück zum Zitat Owen C, Barnett M, Fitzgibbon J. Familial myelodysplasia and acute myeloid leukaemia–a review. Br J Haematol. 2008;140:123–32.PubMedCrossRef Owen C, Barnett M, Fitzgibbon J. Familial myelodysplasia and acute myeloid leukaemia–a review. Br J Haematol. 2008;140:123–32.PubMedCrossRef
21.
Zurück zum Zitat Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J. Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med. 2004;351:2403–7.PubMedCrossRef Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J. Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med. 2004;351:2403–7.PubMedCrossRef
22.
Zurück zum Zitat Godley LA. Inherited predisposition to acute myeloid leukemia. Semin Hematol. 2014;51:306–21.PubMedCrossRef Godley LA. Inherited predisposition to acute myeloid leukemia. Semin Hematol. 2014;51:306–21.PubMedCrossRef
23.
Zurück zum Zitat Tawana K, Wang J, Renneville A, Bödör C, Hills R, Loveday C, et al. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood. 2015;126:1214–23.PubMedCrossRef Tawana K, Wang J, Renneville A, Bödör C, Hills R, Loveday C, et al. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood. 2015;126:1214–23.PubMedCrossRef
24.
Zurück zum Zitat Pabst T, Eyholzer M, Haefliger S, Schardt J, Mueller BU. Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. J Clin Oncol. 2008;26:5088–93.PubMedCrossRef Pabst T, Eyholzer M, Haefliger S, Schardt J, Mueller BU. Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. J Clin Oncol. 2008;26:5088–93.PubMedCrossRef
25.
Zurück zum Zitat Wakita S, Sakaguchi M, Oh I, Kako S, Toya T, Najima Y, et al. Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia. Blood Adv. 2022;6:238–47.PubMedPubMedCentralCrossRef Wakita S, Sakaguchi M, Oh I, Kako S, Toya T, Najima Y, et al. Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia. Blood Adv. 2022;6:238–47.PubMedPubMedCentralCrossRef
26.
Zurück zum Zitat McBride KA, Ballinger ML, Killick E, Kirk J, Tattersall MHN, Eeles RA, et al. Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat Rev Clin Oncol. 2014;11:260–71.PubMedCrossRef McBride KA, Ballinger ML, Killick E, Kirk J, Tattersall MHN, Eeles RA, et al. Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat Rev Clin Oncol. 2014;11:260–71.PubMedCrossRef
27.
Zurück zum Zitat Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 2007;28:622–9.PubMedCrossRef Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 2007;28:622–9.PubMedCrossRef
28.
Zurück zum Zitat Hof J, Krentz S, van Schewick C, Körner G, Shalapour S, Rhein P, et al. Mutations and deletions of the TP53 gene predict nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic leukemia. J Clin Oncol. 2011;29:3185–93.PubMedCrossRef Hof J, Krentz S, van Schewick C, Körner G, Shalapour S, Rhein P, et al. Mutations and deletions of the TP53 gene predict nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic leukemia. J Clin Oncol. 2011;29:3185–93.PubMedCrossRef
29.
Zurück zum Zitat Salmoiraghi S, Montalvo MLG, Ubiali G, Tosi M, Peruta B, Zanghi P, et al. Mutations of TP53 gene in adult acute lymphoblastic leukemia at diagnosis do not affect the achievement of hematologic response but correlate with early relapse and very poor survival. Haematologica. 2016;101:e245–8.PubMedPubMedCentralCrossRef Salmoiraghi S, Montalvo MLG, Ubiali G, Tosi M, Peruta B, Zanghi P, et al. Mutations of TP53 gene in adult acute lymphoblastic leukemia at diagnosis do not affect the achievement of hematologic response but correlate with early relapse and very poor survival. Haematologica. 2016;101:e245–8.PubMedPubMedCentralCrossRef
30.
Zurück zum Zitat Irving JAE, Enshaei A, Parker CA, Sutton R, Kuiper RP, Erhorn A, et al. Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia. Blood. 2016;128:911–22.PubMedPubMedCentralCrossRef Irving JAE, Enshaei A, Parker CA, Sutton R, Kuiper RP, Erhorn A, et al. Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia. Blood. 2016;128:911–22.PubMedPubMedCentralCrossRef
31.
Zurück zum Zitat Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999;23:166–75.PubMedCrossRef Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999;23:166–75.PubMedCrossRef
32.
Zurück zum Zitat Latger-Cannard V, Philippe C, Bouquet A, Baccini V, Alessi M-C, Ankri A, et al. Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders. Orphanet J Rare Dis. 2016;11:49.PubMedPubMedCentralCrossRef Latger-Cannard V, Philippe C, Bouquet A, Baccini V, Alessi M-C, Ankri A, et al. Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders. Orphanet J Rare Dis. 2016;11:49.PubMedPubMedCentralCrossRef
33.
Zurück zum Zitat Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N, et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood. 2002;99:1364–72.PubMedCrossRef Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N, et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood. 2002;99:1364–72.PubMedCrossRef
34.
Zurück zum Zitat Brown AL, Arts P, Carmichael CL, Babic M, Dobbins J, Chong C-E, et al. RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. Blood Adv. 2020;4:1131–44.PubMedPubMedCentralCrossRef Brown AL, Arts P, Carmichael CL, Babic M, Dobbins J, Chong C-E, et al. RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. Blood Adv. 2020;4:1131–44.PubMedPubMedCentralCrossRef
35.
Zurück zum Zitat Churpek JE, Pyrtel K, Kanchi K-L, Shao J, Koboldt D, Miller CA, et al. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood. 2015;126:2484–90.PubMedPubMedCentralCrossRef Churpek JE, Pyrtel K, Kanchi K-L, Shao J, Koboldt D, Miller CA, et al. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood. 2015;126:2484–90.PubMedPubMedCentralCrossRef
36.
Zurück zum Zitat Homan CC, Scott HS, Brown AL. Hereditary platelet disorders associated with germ line variants in RUNX1, ETV6, and ANKRD26. Blood. 2023;141:1533–43.PubMedPubMedCentralCrossRef Homan CC, Scott HS, Brown AL. Hereditary platelet disorders associated with germ line variants in RUNX1, ETV6, and ANKRD26. Blood. 2023;141:1533–43.PubMedPubMedCentralCrossRef
37.
Zurück zum Zitat Wang LC, Swat W, Fujiwara Y, Davidson L, Visvader J, Kuo F, et al. The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow. Genes Dev. 1998;12:2392–402.PubMedPubMedCentralCrossRef Wang LC, Swat W, Fujiwara Y, Davidson L, Visvader J, Kuo F, et al. The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow. Genes Dev. 1998;12:2392–402.PubMedPubMedCentralCrossRef
38.
Zurück zum Zitat Wang LC, Kuo F, Fujiwara Y, Gilliland DG, Golub TR, Orkin SH. Yolk sac angiogenic defect and intra-embryonic apoptosis in mice lacking the Ets-related factor TEL. EMBO J. 1997;16:4374–83.PubMedPubMedCentralCrossRef Wang LC, Kuo F, Fujiwara Y, Gilliland DG, Golub TR, Orkin SH. Yolk sac angiogenic defect and intra-embryonic apoptosis in mice lacking the Ets-related factor TEL. EMBO J. 1997;16:4374–83.PubMedPubMedCentralCrossRef
39.
Zurück zum Zitat Wang L, Hiebert SW. TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. Oncogene. 2001;20:3716–25.PubMedCrossRef Wang L, Hiebert SW. TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. Oncogene. 2001;20:3716–25.PubMedCrossRef
40.
Zurück zum Zitat Nishii R, Baskin-Doerfler R, Yang W, Oak N, Zhao X, Yang W, et al. Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia. Blood. 2021;137:364–73.PubMedPubMedCentralCrossRef Nishii R, Baskin-Doerfler R, Yang W, Oak N, Zhao X, Yang W, et al. Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia. Blood. 2021;137:364–73.PubMedPubMedCentralCrossRef
41.
Zurück zum Zitat Faleschini M, Ammeti D, Papa N, Alfano C, Bottega R, Fontana G, et al. ETV6-related thrombocytopenia: dominant negative effect of mutations as common pathogenic mechanism. Haematologica. 2022;107:2249–54.PubMedPubMedCentralCrossRef Faleschini M, Ammeti D, Papa N, Alfano C, Bottega R, Fontana G, et al. ETV6-related thrombocytopenia: dominant negative effect of mutations as common pathogenic mechanism. Haematologica. 2022;107:2249–54.PubMedPubMedCentralCrossRef
42.
Zurück zum Zitat Hock H, Meade E, Medeiros S, Schindler JW, Valk PJM, Fujiwara Y, et al. Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes Dev. 2004;18:2336–41.PubMedPubMedCentralCrossRef Hock H, Meade E, Medeiros S, Schindler JW, Valk PJM, Fujiwara Y, et al. Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes Dev. 2004;18:2336–41.PubMedPubMedCentralCrossRef
43.
Zurück zum Zitat Vyas H, Alcheikh A, Lowe G, Stevenson WS, Morgan NV, Rabbolini DJ. Prevalence and natural history of variants in the ANKRD26 gene: a short review and update of reported cases. Platelets. 2022;33:1107–12.PubMedPubMedCentralCrossRef Vyas H, Alcheikh A, Lowe G, Stevenson WS, Morgan NV, Rabbolini DJ. Prevalence and natural history of variants in the ANKRD26 gene: a short review and update of reported cases. Platelets. 2022;33:1107–12.PubMedPubMedCentralCrossRef
44.
Zurück zum Zitat Moriyama T, Metzger ML, Wu G, Nishii R, Qian M, Devidas M, et al. Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. Lancet Oncol. 2015;16:1659–66.PubMedPubMedCentralCrossRef Moriyama T, Metzger ML, Wu G, Nishii R, Qian M, Devidas M, et al. Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. Lancet Oncol. 2015;16:1659–66.PubMedPubMedCentralCrossRef
45.
Zurück zum Zitat Pippucci T, Savoia A, Perrotta S, Pujol-Moix N, Noris P, Castegnaro G, et al. Mutations in the 5’ UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. Am J Hum Genet. 2011;88:115–20.PubMedPubMedCentralCrossRef Pippucci T, Savoia A, Perrotta S, Pujol-Moix N, Noris P, Castegnaro G, et al. Mutations in the 5’ UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. Am J Hum Genet. 2011;88:115–20.PubMedPubMedCentralCrossRef
46.
Zurück zum Zitat Noris P, Favier R, Alessi M-C, Geddis AE, Kunishima S, Heller PG, et al. ANKRD26-related thrombocytopenia and myeloid malignancies. Blood. 2013;122:1987–9.PubMedCrossRef Noris P, Favier R, Alessi M-C, Geddis AE, Kunishima S, Heller PG, et al. ANKRD26-related thrombocytopenia and myeloid malignancies. Blood. 2013;122:1987–9.PubMedCrossRef
47.
Zurück zum Zitat Noris P, Perrotta S, Seri M, Pecci A, Gnan C, Loffredo G, et al. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood. 2011;117:6673–80.PubMedCrossRef Noris P, Perrotta S, Seri M, Pecci A, Gnan C, Loffredo G, et al. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood. 2011;117:6673–80.PubMedCrossRef
48.
Zurück zum Zitat Tawana K, Brown AL, Churpek JE. Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges. Br J Haematol. 2022;196:1293–310.PubMedCrossRef Tawana K, Brown AL, Churpek JE. Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges. Br J Haematol. 2022;196:1293–310.PubMedCrossRef
49.
Zurück zum Zitat Perez Botero J, Dugan SN, Anderson MW. ANKRD26-related thrombocytopenia (1993). Perez Botero J, Dugan SN, Anderson MW. ANKRD26-related thrombocytopenia (1993).
50.
Zurück zum Zitat Ovsyannikova GS, Fedorova DV, Tesakov IP, Martyanov AA, Ignatova AA, Ponomarenko EA, et al. Platelet functional abnormalities and clinical presentation in pediatric patients with germline RUNX1, ANKRD26, and ETV6 mutations. Haematologica. 2022;107:2511–6.PubMedPubMedCentralCrossRef Ovsyannikova GS, Fedorova DV, Tesakov IP, Martyanov AA, Ignatova AA, Ponomarenko EA, et al. Platelet functional abnormalities and clinical presentation in pediatric patients with germline RUNX1, ANKRD26, and ETV6 mutations. Haematologica. 2022;107:2511–6.PubMedPubMedCentralCrossRef
51.
Zurück zum Zitat Sahoo SS, Pastor VB, Goodings C, Voss RK, Kozyra EJ, Szvetnik A, et al. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. Nat Med. 2021;27:1806–17.PubMedPubMedCentralCrossRef Sahoo SS, Pastor VB, Goodings C, Voss RK, Kozyra EJ, Szvetnik A, et al. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. Nat Med. 2021;27:1806–17.PubMedPubMedCentralCrossRef
52.
Zurück zum Zitat Nagata Y, Narumi S, Guan Y, Przychodzen BP, Hirsch CM, Makishima H, et al. Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes. Blood. 2018;132:2309–13.PubMedPubMedCentralCrossRef Nagata Y, Narumi S, Guan Y, Przychodzen BP, Hirsch CM, Makishima H, et al. Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes. Blood. 2018;132:2309–13.PubMedPubMedCentralCrossRef
53.
Zurück zum Zitat Sahoo SS, Kozyra EJ, Wlodarski MW. Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes. Best Pract Res Clin Haematol. 2020;33:101197.PubMedPubMedCentralCrossRef Sahoo SS, Kozyra EJ, Wlodarski MW. Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes. Best Pract Res Clin Haematol. 2020;33:101197.PubMedPubMedCentralCrossRef
54.
Zurück zum Zitat Wlodarski MW, Hirabayashi S, Pastor V, Starý J, Hasle H, Masetti R, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016;127:1387–97.PubMedCrossRef Wlodarski MW, Hirabayashi S, Pastor V, Starý J, Hasle H, Masetti R, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016;127:1387–97.PubMedCrossRef
55.
Zurück zum Zitat Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123:809–21.PubMedPubMedCentralCrossRef Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123:809–21.PubMedPubMedCentralCrossRef
56.
Zurück zum Zitat Ishida H, Imai K, Honma K, Tamura S-I, Imamura T, Ito M, et al. GATA-2 anomaly and clinical phenotype of a sporadic case of lymphedema, dendritic cell, monocyte, B- and NK-cell (DCML) deficiency, and myelodysplasia. Eur J Pediatr. 2012;171:1273–6.PubMedCrossRef Ishida H, Imai K, Honma K, Tamura S-I, Imamura T, Ito M, et al. GATA-2 anomaly and clinical phenotype of a sporadic case of lymphedema, dendritic cell, monocyte, B- and NK-cell (DCML) deficiency, and myelodysplasia. Eur J Pediatr. 2012;171:1273–6.PubMedCrossRef
57.
Zurück zum Zitat Hahn CN, Chong C-E, Carmichael CL, Wilkins EJ, Brautigan PJ, Li X-C, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 2011;43:1012–7.PubMedPubMedCentralCrossRef Hahn CN, Chong C-E, Carmichael CL, Wilkins EJ, Brautigan PJ, Li X-C, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 2011;43:1012–7.PubMedPubMedCentralCrossRef
58.
Zurück zum Zitat Calvo KR, Hickstein DD. The spectrum of GATA2 deficiency syndrome. Blood. 2023;141:1524–32.PubMedCrossRef Calvo KR, Hickstein DD. The spectrum of GATA2 deficiency syndrome. Blood. 2023;141:1524–32.PubMedCrossRef
59.
Zurück zum Zitat Nichols-Vinueza DX, Parta M, Shah NN, Cuellar-Rodriguez JM, Bauer TR, West RR, et al. Donor source and post-transplantation cyclophosphamide influence outcome in allogeneic stem cell transplantation for GATA2 deficiency. Br J Haematol. 2022;196:169–78.PubMedCrossRef Nichols-Vinueza DX, Parta M, Shah NN, Cuellar-Rodriguez JM, Bauer TR, West RR, et al. Donor source and post-transplantation cyclophosphamide influence outcome in allogeneic stem cell transplantation for GATA2 deficiency. Br J Haematol. 2022;196:169–78.PubMedCrossRef
60.
Zurück zum Zitat Narumi S, Amano N, Ishii T, Katsumata N, Muroya K, Adachi M, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 2016;48:792–7.PubMedCrossRef Narumi S, Amano N, Ishii T, Katsumata N, Muroya K, Adachi M, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 2016;48:792–7.PubMedCrossRef
61.
Zurück zum Zitat Chen D-H, Below JE, Shimamura A, Keel SB, Matsushita M, Wolff J, et al. Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L. Am J Hum Genet. 2016;98:1146–58.PubMedPubMedCentralCrossRef Chen D-H, Below JE, Shimamura A, Keel SB, Matsushita M, Wolff J, et al. Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L. Am J Hum Genet. 2016;98:1146–58.PubMedPubMedCentralCrossRef
62.
Zurück zum Zitat Buonocore F, Kühnen P, Suntharalingham JP, Del Valle I, Digweed M, Stachelscheid H, et al. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J Clin Investig. 2017;127:1700–13.PubMedPubMedCentralCrossRef Buonocore F, Kühnen P, Suntharalingham JP, Del Valle I, Digweed M, Stachelscheid H, et al. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J Clin Investig. 2017;127:1700–13.PubMedPubMedCentralCrossRef
63.
Zurück zum Zitat Tesi B, Davidsson J, Voss M, Rahikkala E, Holmes TD, Chiang SCC, et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. Blood. 2017;129:2266–79.PubMedPubMedCentralCrossRef Tesi B, Davidsson J, Voss M, Rahikkala E, Holmes TD, Chiang SCC, et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. Blood. 2017;129:2266–79.PubMedPubMedCentralCrossRef
64.
Zurück zum Zitat Pastor VB, Sahoo SS, Boklan J, Schwabe GC, Saribeyoglu E, Strahm B, et al. Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7. Haematologica. 2018;103:427–37.PubMedPubMedCentralCrossRef Pastor VB, Sahoo SS, Boklan J, Schwabe GC, Saribeyoglu E, Strahm B, et al. Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7. Haematologica. 2018;103:427–37.PubMedPubMedCentralCrossRef
65.
Zurück zum Zitat Schwartz JR, Wang S, Ma J, Lamprecht T, Walsh M, Song G, et al. Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome. Leukemia. 2017;31:1827–30.PubMedPubMedCentralCrossRef Schwartz JR, Wang S, Ma J, Lamprecht T, Walsh M, Song G, et al. Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome. Leukemia. 2017;31:1827–30.PubMedPubMedCentralCrossRef
67.
Zurück zum Zitat Bluteau O, Sebert M, Leblanc T, Peffault de Latour R, Quentin S, Lainey E, et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood. 2018;131:717–32.PubMedCrossRef Bluteau O, Sebert M, Leblanc T, Peffault de Latour R, Quentin S, Lainey E, et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood. 2018;131:717–32.PubMedCrossRef
69.
Zurück zum Zitat Dietz AC, Orchard PJ, Baker KS, Giller RH, Savage SA, Alter BP, et al. Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita. Bone Marrow Transplant. 2011;46:98–104.PubMedCrossRef Dietz AC, Orchard PJ, Baker KS, Giller RH, Savage SA, Alter BP, et al. Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita. Bone Marrow Transplant. 2011;46:98–104.PubMedCrossRef
70.
Zurück zum Zitat Nishio N, Takahashi Y, Ohashi H, Doisaki S, Muramatsu H, Hama A, et al. Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita. Pediatr Transplant. 2011;15:161–6.PubMedCrossRef Nishio N, Takahashi Y, Ohashi H, Doisaki S, Muramatsu H, Hama A, et al. Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita. Pediatr Transplant. 2011;15:161–6.PubMedCrossRef
71.
Zurück zum Zitat Ayas M, Nassar A, Hamidieh AA, Kharfan-Dabaja M, Othman TB, Elhaddad A, et al. Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure. Bone Marrow Transplant. 2013;48:1168–72.PubMedCrossRef Ayas M, Nassar A, Hamidieh AA, Kharfan-Dabaja M, Othman TB, Elhaddad A, et al. Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure. Bone Marrow Transplant. 2013;48:1168–72.PubMedCrossRef
72.
Zurück zum Zitat Reilly CR, Shimamura A. Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: biological insights and clinical advances. Blood. 2023;141:1513–23.PubMedCrossRef Reilly CR, Shimamura A. Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: biological insights and clinical advances. Blood. 2023;141:1513–23.PubMedCrossRef
73.
Zurück zum Zitat Kennedy AL, Myers KC, Bowman J, Gibson CJ, Camarda ND, Furutani E, et al. Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome. Nat Commun. 2021;12:1334.PubMedPubMedCentralCrossRef Kennedy AL, Myers KC, Bowman J, Gibson CJ, Camarda ND, Furutani E, et al. Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome. Nat Commun. 2021;12:1334.PubMedPubMedCentralCrossRef
74.
Zurück zum Zitat Lindsley RC, Saber W, Mar BG, Redd R, Wang T, Haagenson MD, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376:536–47.PubMedPubMedCentralCrossRef Lindsley RC, Saber W, Mar BG, Redd R, Wang T, Haagenson MD, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376:536–47.PubMedPubMedCentralCrossRef
75.
Zurück zum Zitat Myers KC, Furutani E, Weller E, Siegele B, Galvin A, Arsenault V, et al. Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study. Lancet Haematol. 2020;7:e238–46.PubMedCrossRef Myers KC, Furutani E, Weller E, Siegele B, Galvin A, Arsenault V, et al. Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study. Lancet Haematol. 2020;7:e238–46.PubMedCrossRef
76.
Zurück zum Zitat Chao EC, Astbury C, Deignan JL, Pronold M, Reddi HV, Weitzel JN, et al. Incidental detection of acquired variants in germline genetic and genomic testing: a points to consider statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23:1179–84.PubMedCrossRef Chao EC, Astbury C, Deignan JL, Pronold M, Reddi HV, Weitzel JN, et al. Incidental detection of acquired variants in germline genetic and genomic testing: a points to consider statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23:1179–84.PubMedCrossRef
77.
Zurück zum Zitat Kanagal-Shamanna R. Never too old to blame it on your (inherited) genes. Blood. 2022;140:2521–3.PubMedCrossRef Kanagal-Shamanna R. Never too old to blame it on your (inherited) genes. Blood. 2022;140:2521–3.PubMedCrossRef
Metadaten
Titel
Molecular pathophysiology of germline mutations in acute myeloid leukemia
verfasst von
Yasunobu Nagata
Publikationsdatum
16.08.2024
Verlag
Springer Nature Singapore
Erschienen in
International Journal of Hematology / Ausgabe 4/2024
Print ISSN: 0925-5710
Elektronische ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-024-03824-x

Neu im Fachgebiet Onkologie

Metastasiertes CRC: besser Checkpointhemmer im Doppelpack!

Die Kombination von Nivolumab plus Ipilimumab ist beim metastasierten Kolorektalkarzinom mit MSI-H- oder dMMR klar im Vorteil gegenüber einer Nivolumab-Monotherapie: Das Progressionsrisiko war damit in einer Phase-3-Studie um 38% reduziert.

Große Trinkmengen bei Blasentumoren möglicherweise von Nachteil

Beim nicht-muskelinvasiven Blasenkrebs scheint eine hohe Flüssigkeitszufuhr keinen schützenden Effekt in Bezug auf das Risiko eines Rezidivs oder einer Krankheitsprogression zu haben. Eine niederländische Studie legt sogar nahe, dass große Trinkmengen das Fortschreiten der Erkrankung begünstigen könnten.

Höhere Trefferquoten bei Brustkrebsscreening dank KI?

Künstliche Intelligenz unterstützt bei der Auswertung von Mammografie-Screenings und senkt somit den Arbeitsaufwand für Radiologen. Wie wirken sich diese Technologien auf die Trefferquote und die Falsch-positiv-Rate aus? Das hat jetzt eine Studie aus Schweden untersucht.

Urintest auf Prostatakrebs funktioniert mit Erststrahlurin

Ein auf die Expression von 18 Genen gestützter Urintest auf klinisch signifikanten Prostatakrebs könnte offenbar auch in Anwendung auf Erststrahlurin dazu dienen, unnötige Biopsien zu vermeiden.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.