Skip to main content
Erschienen in: International Journal of Hematology 3/2023

10.03.2023 | Case Report

Unrelated hematopoietic stem cell transplantation for familial platelet disorder/acute myeloid leukemia with germline RUNX1 mutations

verfasst von: Kazunori Toratani, Mizuki Watanabe, Junya Kanda, Tomomi Oka, Mizuki Hyuga, Yasuyuki Arai, Makoto Iwasaki, Maki Sakurada, Yasuhito Nannya, Seishi Ogawa, Takahiro Yamada, Akifumi Takaori-Kondo

Erschienen in: International Journal of Hematology | Ausgabe 3/2023

Einloggen, um Zugang zu erhalten

Abstract

Germline mutations in RUNX1 result in rare autosomal-dominant familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML). As genetic analysis is becoming increasingly prevalent, the diagnosis rate of FPD/AML is expected to increase. In this report, we present two pedigrees, one diagnosed molecularly and another highly suspected to be FPD/AML, whose members both received allogeneic hematopoietic stem cell transplantation (HSCT). Both pedigrees had a family history of thrombocytopenia, platelet dysfunction, and hematological malignancies. One family inherited a frameshift mutation (p.P240fs) of RUNX1, a known pathogenic variant. Another family inherited a point mutation (p.G168R) in the runt-homology domain, the clinical significance of which is uncertain at this point. As this mutation was completely absent from all population databases and had a relatively high REVEL score of 0.947, we thought that it would be dangerous to ignore its possible pathogenicity. Consequently, we avoided choosing HSCT donors from relatives of both families and performed HSCT from unrelated donors. In conclusion, our experience with two families of FPD/AML highlights the importance of searching for gene mutations associated with germline predisposition and indicates the necessity of developing a donor coordination system for FPD/AML patients, as well as a support system for families.
Literatur
1.
Zurück zum Zitat Vradii D, Zaidi SK, Lian JB, van Wijnen AJ, Stein JL, Stein GS. Point mutation in AML1 disrupts subnuclear targeting, prevents myeloid differentiation, and effects a transformation-like phenotype. Proc Natl Acad Sci USA. 2005;102:7174–9.CrossRefPubMedPubMedCentral Vradii D, Zaidi SK, Lian JB, van Wijnen AJ, Stein JL, Stein GS. Point mutation in AML1 disrupts subnuclear targeting, prevents myeloid differentiation, and effects a transformation-like phenotype. Proc Natl Acad Sci USA. 2005;102:7174–9.CrossRefPubMedPubMedCentral
2.
Zurück zum Zitat Brown AL, Arts P, Carmichchael CL, Babic M, Dobbins J, Chong CE, et al. RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. Blood Adv. 2020;4:1131–44.CrossRefPubMedPubMedCentral Brown AL, Arts P, Carmichchael CL, Babic M, Dobbins J, Chong CE, et al. RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. Blood Adv. 2020;4:1131–44.CrossRefPubMedPubMedCentral
3.
Zurück zum Zitat Luo X, Feurstein S, Mohan S, Porter CC, Jackson SA, Keel S, et al. ClinGen myeloid malignancy variant curation expert panel recommendations for germline RUNX1 variants. Blood Adv. 2019;3:2962–79.CrossRefPubMedPubMedCentral Luo X, Feurstein S, Mohan S, Porter CC, Jackson SA, Keel S, et al. ClinGen myeloid malignancy variant curation expert panel recommendations for germline RUNX1 variants. Blood Adv. 2019;3:2962–79.CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.CrossRefPubMedPubMedCentral Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99:877–85.CrossRefPubMedPubMedCentral Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99:877–85.CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat Kanagal-Shamanna R, Loghavi S, DiNardo CD, Medeiros LJ, Garcia-Manero G, Jabbour E, et al. Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation. Haematologica. 2017;102:1661–70.CrossRefPubMedPubMedCentral Kanagal-Shamanna R, Loghavi S, DiNardo CD, Medeiros LJ, Garcia-Manero G, Jabbour E, et al. Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation. Haematologica. 2017;102:1661–70.CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat DiNardo CD, Bannon SA, Routbort M, Franklin A, Mork M, Armanios M, et al. Evaluation of patients and families with concern for predispositions to hematologic malignancies within the hereditary hematologic malignancy clinic (HHMC). Clin Lymphoma Myeloma Leuk. 2016;16:417-428.e2.CrossRefPubMedPubMedCentral DiNardo CD, Bannon SA, Routbort M, Franklin A, Mork M, Armanios M, et al. Evaluation of patients and families with concern for predispositions to hematologic malignancies within the hereditary hematologic malignancy clinic (HHMC). Clin Lymphoma Myeloma Leuk. 2016;16:417-428.e2.CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat Osato M, Asou N, Abdalla E, Hoshino K, Yamasaki H, Okubo T, et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2αB gene associated with myeloblastic leukemias. Blood. 1999;93:1817–24.CrossRefPubMed Osato M, Asou N, Abdalla E, Hoshino K, Yamasaki H, Okubo T, et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2αB gene associated with myeloblastic leukemias. Blood. 1999;93:1817–24.CrossRefPubMed
9.
Zurück zum Zitat Deltcheva E, Nimmo R. RUNX transcription factors at the interface of stem cells and cancer. Biochem J. 2017;474:1755–68.CrossRefPubMed Deltcheva E, Nimmo R. RUNX transcription factors at the interface of stem cells and cancer. Biochem J. 2017;474:1755–68.CrossRefPubMed
10.
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.CrossRefPubMed 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.CrossRefPubMed
11.
Zurück zum Zitat Simon L, Spinella JF, Yao CY, Lavallee VP, Boivin I, Boucher G, et al. High frequency of germline RUNX1 mutations in patients with RUNX1-mutated AML. Blood. 2020;135:1882–6.CrossRefPubMed Simon L, Spinella JF, Yao CY, Lavallee VP, Boivin I, Boucher G, et al. High frequency of germline RUNX1 mutations in patients with RUNX1-mutated AML. Blood. 2020;135:1882–6.CrossRefPubMed
12.
Zurück zum Zitat Ciurea SO. Considerations for haploidentical versus unrelated donor transplants. Bone Marrow Transplant. 2019;54:738–42.CrossRefPubMed Ciurea SO. Considerations for haploidentical versus unrelated donor transplants. Bone Marrow Transplant. 2019;54:738–42.CrossRefPubMed
13.
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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Berger G, van den Berg E, Sikkema-Raddatz B, Abbott KM, Sinke RJ, Bungener LB, et al. Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation. Leukemia. 2017;31:520–2.CrossRefPubMed Berger G, van den Berg E, Sikkema-Raddatz B, Abbott KM, Sinke RJ, Bungener LB, et al. Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation. Leukemia. 2017;31:520–2.CrossRefPubMed
15.
Zurück zum Zitat Kobayashi S, Kobayashi A, Osawa Y, Nagao S, Takano K, Okada Y, et al. Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation. Leukemia. 2017;31:1020–2.CrossRefPubMed Kobayashi S, Kobayashi A, Osawa Y, Nagao S, Takano K, Okada Y, et al. Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation. Leukemia. 2017;31:1020–2.CrossRefPubMed
Metadaten
Titel
Unrelated hematopoietic stem cell transplantation for familial platelet disorder/acute myeloid leukemia with germline RUNX1 mutations
verfasst von
Kazunori Toratani
Mizuki Watanabe
Junya Kanda
Tomomi Oka
Mizuki Hyuga
Yasuyuki Arai
Makoto Iwasaki
Maki Sakurada
Yasuhito Nannya
Seishi Ogawa
Takahiro Yamada
Akifumi Takaori-Kondo
Publikationsdatum
10.03.2023
Verlag
Springer Nature Singapore
Erschienen in
International Journal of Hematology / Ausgabe 3/2023
Print ISSN: 0925-5710
Elektronische ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-023-03575-1

Weitere Artikel der Ausgabe 3/2023

International Journal of Hematology 3/2023 Zur Ausgabe

Mehr Lebenszeit mit Abemaciclib bei fortgeschrittenem Brustkrebs?

24.05.2024 Mammakarzinom Nachrichten

In der MONARCHE-3-Studie lebten Frauen mit fortgeschrittenem Hormonrezeptor-positivem, HER2-negativem Brustkrebs länger, wenn sie zusätzlich zu einem nicht steroidalen Aromatasehemmer mit Abemaciclib behandelt wurden; allerdings verfehlte der numerische Zugewinn die statistische Signifikanz.

ADT zur Radiatio nach Prostatektomie: Wenn, dann wohl länger

24.05.2024 Prostatakarzinom Nachrichten

Welchen Nutzen es trägt, wenn die Strahlentherapie nach radikaler Prostatektomie um eine Androgendeprivation ergänzt wird, hat die RADICALS-HD-Studie untersucht. Nun liegen die Ergebnisse vor. Sie sprechen für länger dauernden Hormonentzug.

Das sind die führenden Symptome junger Darmkrebspatienten

Darmkrebserkrankungen in jüngeren Jahren sind ein zunehmendes Problem, das häufig längere Zeit übersehen wird, gerade weil die Patienten noch nicht alt sind. Welche Anzeichen Ärzte stutzig machen sollten, hat eine Metaanalyse herausgearbeitet.

„Überwältigende“ Evidenz für Tripeltherapie beim metastasierten Prostata-Ca.

22.05.2024 Prostatakarzinom Nachrichten

Patienten mit metastasiertem hormonsensitivem Prostatakarzinom sollten nicht mehr mit einer alleinigen Androgendeprivationstherapie (ADT) behandelt werden, mahnt ein US-Team nach Sichtung der aktuellen Datenlage. Mit einer Tripeltherapie haben die Betroffenen offenbar die besten Überlebenschancen.

Update Onkologie

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