Hereditary Hematopoietic Malignancies: Considerations for Optimizing Diagnosis and Management

Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, et al. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140:1200–28. https://doi.org/10.1182/BLOOD.2022015850.

Article  CAS  PubMed  PubMed Central  Google Scholar 

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. https://doi.org/10.1038/S41375-022-01613-1.

Article  PubMed  PubMed Central  Google Scholar 

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. https://doi.org/10.1182/BLOOD.2022015790.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Godley LA, DiNardo CD, Bolton K. Germline predisposition in hematologic malignancies: testing, management, and implications. Am Soc Clin Oncol Educ Book Am Soc Clin Oncol Annu Meet. 2024;44. https://doi.org/10.1200/EDBK_432218.

Kraft IL, Godley LA. Identifying potential germline variants from sequencing hematopoietic malignancies. Hematol Am Soc Hematol Educ Progr. 2020;2020:219–27. https://doi.org/10.1182/hematology.2020006910.

Article  Google Scholar 

Subbiah V, Kurzrock R. Universal germline and tumor genomic testing needed to win the war against cancer: genomics is the diagnosis. J Clin Oncol. 2023;41:3100–3. https://doi.org/10.1200/JCO.22.02833.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140:1345–77. https://doi.org/10.1182/BLOOD.2022016867.

Article  PubMed  Google Scholar 

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. https://doi.org/10.1038/13793.

Article  CAS  PubMed  Google Scholar 

Homan CC, King-Smith SL, Lawrence DM, Arts P, Feng J, Andrews J, et al. The RUNX1 database (RUNX1db): establishment of an expert curated RUNX1 registry and genomics database as a public resource for Familial platelet disorder with myeloid malignancy. Haematologica. 2021;106:3004–7. https://doi.org/10.3324/HAEMATOL.2021.278762.

Article  PubMed  PubMed Central  Google Scholar 

PDQ Cancer Genetics Editorial Board. RUNX1-Familial Platelet Disorder (PDQ®): Health Professional Version. PDQ Cancer Inf Summ; 2002.

Aneja K, Jalagadugula G, Mao G, Singh A, Rao AK. Mechanism of platelet factor 4 (PF4) deficiency with RUNX1 haplodeficiency: RUNX1 is a transcriptional regulator of PF4. J Thromb Haemost. 2011;9:383–91. https://doi.org/10.1111/j.1538-7836.2010.04154.x.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Brunet J, Badin M, Chong M, Iyer J, Tasneem S, Graf L, et al. Bleeding risks for uncharacterized platelet function disorders. Res Pract Thromb Haemost. 2020;4:799–806. https://doi.org/10.1002/rth2.12374.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Anderst J, Carpenter SL, Abshire TC, Killough E. Evaluation for bleeding disorders in suspected child abuse. Pediatrics 2022;150. https://doi.org/10.1542/PEDS.2022-059276.

Balduini CL, Savoia A, Seri M. Inherited thrombocytopenias frequently diagnosed in adults. J Thromb Haemost. 2013;11:1006–19. https://doi.org/10.1111/jth.12196.

Article  CAS  PubMed  Google Scholar 

Cunningham L, Merguerian M, Calvo KR, Davis J, Deuitch NT, Dulau-Florea A, et al. Natural history study of patients with Familial platelet disorder with associated myeloid malignancy. Blood. 2023;142:2146–58. https://doi.org/10.1182/BLOOD.2023019746.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yu K, Deuitch N, Merguerian M, Cunningham L, Davis J, Bresciani E, et al. Genomic landscape of patients with germline RUNX1 variants and Familial platelet disorder with myeloid malignancy. Blood Adv. 2024;8:497–511. https://doi.org/10.1182/BLOODADVANCES.2023011165.

Article  CAS  PubMed  Google Scholar 

Kajdic A, Deuitch NT, Bresciani E, Davis J, Craft K, Chong S, et al. Genetic testing to identify hereditary predispositions to haematological malignancy is critical prior to allogenic Haematopoietic cell transplant. Br J Haematol. 2025;206. https://doi.org/10.1111/BJH.19989.

Li Y, Yang W, Devidas M, Winter SS, Kesserwan C, Yang W, et al. Germline RUNX1 variation and predisposition to childhood acute lymphoblastic leukemia. J Clin Invest. 2021;131. https://doi.org/10.1172/JCI147898.

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. https://doi.org/10.3324/HAEMATOL.2017.167726.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Brown AL, Arts P, Carmichael 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. https://doi.org/10.1182/BLOODADVANCES.2019000901.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Avagyan S, Brown AL. To T or not to B: germline RUNX1 mutation preferences in pediatric ALL predisposition. J Clin Invest. 2021;131. https://doi.org/10.1172/JCI152464.

Bagla S, Regling KA, Wakeling EN, Gadgeel M, Buck S, Zaidi AU, et al. Distinctive phenotypes in two children with novel germline RUNX1 mutations - one with myeloid malignancy and increased fetal hemoglobin. Pediatr Hematol Oncol. 2020;38:65–79. https://doi.org/10.1080/08880018.2020.1814463.

Article  CAS  PubMed  Google Scholar 

Antony-Debré I, Manchev VT, Balayn N, Bluteau D, Tomowiak C, Legrand C, et al. Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia. Blood. 2015;125:930–40. https://doi.org/10.1182/BLOOD-2014-06-585513.

Article  PubMed  PubMed Central  Google Scholar 

Abelson S, Collord G, Ng SWK, Weissbrod O, Mendelson Cohen N, Niemeyer E, et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature. 2018;559:400–4. https://doi.org/10.1038/S41586-018-0317-6.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Antony-Debré I, Duployez N, Bucci M, Geffroy S, Micol JB, Renneville A, et al. Somatic mutations associated with leukemic progression of Familial platelet disorder with predisposition to acute myeloid leukemia. Leukemia. 2016;30:999–1002. https://doi.org/10.1038/LEU.2015.236.

Article  PubMed  Google Scholar 

Bellissimo DC, Chen CH, Zhu Q, Bagga S, Lee CT, He B, et al. Runx1 negatively regulates inflammatory cytokine production by neutrophils in response to Toll-like receptor signaling. Blood Adv. 2020;4:1145–58. https://doi.org/10.1182/BLOODADVANCES.2019000785.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mohammadhosseini M, Enright T, Duvall A, Chitsazan A, Lin HY, Ors A, et al. Targeting the CD74 signaling axis suppresses inflammation and rescues defective hematopoiesis in RUNX1–familial platelet disorder. Sci Transl Med. 2025;17. https://doi.org/10.1126/SCITRANSLMED.ADN9832.

Barrett M, Hand CK, Shanahan F, Murphy T, O’Toole PW. Mutagenesis by microbe: the role of the microbiota in shaping the Cancer genome. Trends Cancer. 2020;6:277–87. https://doi.org/10.1016/j.trecan.2020.01.019.

Article  CAS  PubMed  Google Scholar 

Hendricks RM, Kim J, Haley JS, Ramos ML, Mirshahi UL, Carey DJ et al. Genome-first determination of the prevalence and penetrance of eight germline myeloid malignancy predisposition genes: a study of two population-based cohorts. Leukemia 2024;39. https://doi.org/10.1038/S41375-024-02436-Y.

Schaefer EJ, Wang HC, Karp HQ, Meyer CA, Cejas P, Gearhart MD, et al. BCOR and BCORL1 mutations drive epigenetic reprogramming and oncogenic signaling by unlinking PRC1.1 from target genes. Blood Cancer Discov. 2022;3:116–35. https://doi.org/10.1158/2643-3230.BCD-21-0115.

Article  PubMed  PubMed Central  Google Scholar 

Revy P, Kannengiesser C, Bertuch AA. Genetics of human telomere biology disorders. Nat Rev Genet 2022 242. 2022;24:86–108. https://doi.org/10.1038/s41576-022-00527-z.

Article  CAS  Google Scholar 

Kam MLW, Nguyen TTT, Ngeow JYY. Telomere biology disorders. Npj Genomic Med. 2021;6:1–13. https://doi.org/10.1038/s41525-021-00198-5.

Article  CAS  Google Scholar 

Townsley DM, Dumitriu B, Young NS. Bone marrow failure and the telomeropathies. Blood. 2014;124:2775–83. https://doi.org/10.1182/BLOOD-2014-05-526285.

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