Abstract
Although much work has focused on the elucidation of somatic alterations that drive the development of acute leukaemias and other haematopoietic diseases, it has become increasingly recognized that germline mutations are common in many of these neoplasms. In this Review, we highlight the different genetic pathways impacted by germline mutations that can ultimately lead to the development of familial and sporadic haematological malignancies, including acute lymphoblastic leukaemia, acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Many of the genes disrupted by somatic mutations in these diseases (for example, TP53, RUNX1, IKZF1 and ETV6) are the same as those that harbour germline mutations in children and adolescents who develop these malignancies. Moreover, the presumption that familial leukaemias only present in childhood is no longer true, in large part due to the numerous studies demonstrating germline DDX41 mutations in adults with MDS and AML. Lastly, we highlight how different cooperating events can influence the ultimate phenotype in these different familial leukaemia syndromes.
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References
The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020).
Zhang, J. et al. Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 373, 2336–2346 (2015). This seminal study estimates the prevalence of deleterious germline mutations in childhood cancer, based on interrogation of a panel of genes.
Grobner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018).
Parsons, D. W. et al. Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncol. 2, 616–624 (2016).
Huang, K. L. et al. Pathogenic germline variants in 10,389 adult cancers. Cell 173, 355–370.e14 (2018).
Arber, D. A. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127, 2391–2405 (2016).
Godley, L. A. Inherited predisposition to acute myeloid leukemia. Semin. Hematol. 51, 306–321 (2014).
Churchman, M. L. et al. Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia. Cancer Cell 33, 937–948.e8 (2018). This paper identifies germline non-silent IKZF1 variants in familial and sporadic ALL, showing that many of the germline variants are more deleterious than previously identified somatic variants.
Qian, M. et al. Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics. Blood 133, 724–729 (2019).
Moriyama, T. et al. Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. Lancet Oncol. 16, 1659–1666 (2015).
Topka, S. et al. Germline ETV6 mutations confer susceptibility to acute lymphoblastic leukemia and thrombocytopenia. PLoS Genet. 11, e1005262 (2015). This study is one of several that identify germline ETV6 variants associated with ALL and thrombocytopenia.
Shah, S. et al. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat. Genet. 45, 1226–1231 (2013). This paper identifies germline PAX5 variants as causal in familial B-ALL with loss of chromosome 9p leading to hemizygosity of the variant allele.
Perez-Andreu, V. et al. Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nat. Genet. 45, 1494–1498 (2013). This paper presents an example of a GWAS showing association of a germline SNP (in GATA3) with a specific subtype and ancestry of B-ALL.
Polprasert, C. et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell 27, 658–670 (2015). This comprehensive study evaluates the frequency of germline and somatic DDX41 mutations in myeloid malignancies.
Pastor, V. B. et al. Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7. Haematologica 103, 427–437 (2018).
Schwartz, J. R. et al. Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome. Leukemia 31, 1827–1830 (2017).
Narumi, S. et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat. Genet. 48, 792–797 (2016). This paper presents the first description of germline SAMD9 mutations in children with MIRAGE syndrome.
Tesi, B. et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. Blood 129, 2266–2279 (2017).
Wong, J. C. et al. Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes. JCI Insight 3, e121086 (2018). This work uses historical samples to demonstrate germline mutations in SAMD9 and SAMD9L in families with myelodysplasia and leukaemia syndrome with monosomy, and illuminates the variety of revertant and cooperating mutations that influence clinical phenotypes.
Mangaonkar, A. A. & Patnaik, M. M. Hereditary predisposition to hematopoietic neoplasms: when bloodline matters for blood cancers. Mayo Clin. Proc. 95, 1482–1498 (2020).
Furutani, E. & Shimamura, A. Germline genetic predisposition to hematologic malignancy. J. Clin. Oncol. 35, 1018–1028 (2017).
Porter, C. C. et al. Recommendations for surveillance for children with leukemia-predisposing conditions. Clin. Cancer Res. 23, e14–e22 (2017).
Wegman-Ostrosky, T. & Savage, S. A. The genomics of inherited bone marrow failure: from mechanism to the clinic. Br. J. Haematol. 177, 526–542 (2017).
Faber, Z. J. et al. The genomic landscape of core-binding factor acute myeloid leukemias. Nat. Genet. 48, 1551–1556 (2016).
Gaidzik, V. I. et al. RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features. Leukemia 30, 2160–2168 (2016).
Grossmann, V. et al. Prognostic relevance of RUNX1 mutations in T-cell acute lymphoblastic leukemia. Haematologica 96, 1874–1877 (2011).
Osato, M. et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2αB gene associated with myeloblastic leukemias. Blood 93, 1817–1824 (1999).
Zelent, A., Greaves, M. & Enver, T. Role of the TEL–AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia. Oncogene 23, 4275–4283 (2004).
Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).
Latger-Cannard, V. 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. 11, 49 (2016).
Song, W. J. et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat. Genet. 23, 166–175 (1999). This paper links familial platelet disorder with predisposition to AML with germline alterations in RUNX1.
Antony-Debre, I. et al. Somatic mutations associated with leukemic progression of familial platelet disorder with predisposition to acute myeloid leukemia. Leukemia 30, 999–1002 (2016).
Michaud, J. 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 99, 1364–1372 (2002).
Brown, A. L. et al. RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. Blood Adv. 4, 1131–1144 (2020).
Churpek, J. E. et al. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood 126, 2484–2490 (2015).
Preudhomme, C. et al. High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder. Blood 113, 5583–5587 (2009).
Shiba, N. et al. CBL mutation in chronic myelomonocytic leukemia secondary to familial platelet disorder with propensity to develop acute myeloid leukemia (FPD/AML). Blood 119, 2612–2614 (2012).
Pabst, T. et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-α (C/EBPα), in acute myeloid leukemia. Nat. Genet. 27, 263–270 (2001).
Frohling, S. et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J. Clin. Oncol. 22, 624–633 (2004).
Pabst, T., Eyholzer, M., Haefliger, S., Schardt, J. & Mueller, B. U. Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. J. Clin. Oncol. 26, 5088–5093 (2008).
Tawana, K. et al. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood 126, 1214–1223 (2015). This work studies diagnosis and relapse leukaemia samples from patients with germline CEBPA mutations and demonstrates that disease recurrence is commonly driven by new, independent clones rather than re-emergence of an existing clone present at diagnosis.
Smith, M. L., Cavenagh, J. D., Lister, T. A. & Fitzgibbon, J. Mutation of CEBPA in familial acute myeloid leukemia. N. Engl. J. Med. 351, 2403–2407 (2004).
Taskesen, E. et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 117, 2469–2475 (2011).
Pathak, A. et al. Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family. Haematologica 101, 846–852 (2016).
Wlodarski, M. W., Collin, M. & Horwitz, M. S. GATA2 deficiency and related myeloid neoplasms. Semin. Hematol. 54, 81–86 (2017).
Wlodarski, M. W. et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood 127, 1387–1397 (2016). This definitive and comprehensive study demonstrates the prevalence of germline GATA2 mutations in paediatric MDS.
Cortes-Lavaud, X. et al. GATA2 germline mutations impair GATA2 transcription, causing haploinsufficiency: functional analysis of the p.Arg396Gln mutation. J. Immunol. 194, 2190–2198 (2015).
Hsu, A. P. et al. GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood 121, 3830–3837 (2013).
Wehr, C. et al. A novel disease-causing synonymous exonic mutation in GATA2 affecting RNA splicing. Blood 132, 1211–1215 (2018).
Kozyra, E. J. et al. Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency. Leukemia 34, 2673–2687 (2020).
Cavalcante de Andrade Silva, M. et al. Breaking the spatial constraint between neighboring zinc fingers: a new germline mutation in GATA2 deficiency syndrome. Leukemia https://doi.org/10.1038/s41375-020-0820-2 (2020).
Yoshida, M. et al. Prevalence of germline GATA2 and SAMD9/9L variants in paediatric haematological disorders with monosomy 7. Br. J. Haematol. 191, 835–843 (2020).
Micol, J. B. & Abdel-Wahab, O. Collaborating constitutive and somatic genetic events in myeloid malignancies: ASXL1 mutations in patients with germline GATA2 mutations. Haematologica 99, 201–203 (2014).
West, R. R., Hsu, A. P., Holland, S. M., Cuellar-Rodriguez, J. & Hickstein, D. D. Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation. Haematologica 99, 276–281 (2014).
Bodor, C. et al. Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival. Haematologica 97, 890–894 (2012).
Al Seraihi, A. F. et al. GATA2 monoallelic expression underlies reduced penetrance in inherited GATA2-mutated MDS/AML. Leukemia 32, 2502–2507 (2018).
Rocak, S. & Linder, P. DEAD-box proteins: the driving forces behind RNA metabolism. Nat. Rev. Mol. Cell Biol. 5, 232–241 (2004).
Fullam, A. & Schroder, M. DExD/H-box RNA helicases as mediators of anti-viral innate immunity and essential host factors for viral replication. Biochim. Biophys. Acta 1829, 854–865 (2013).
Zhang, Z. et al. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat. Immunol. 12, 959–965 (2011).
Lee, K. G. et al. Bruton’s tyrosine kinase phosphorylates DDX41 and activates its binding of dsDNA and STING to initiate type 1 interferon response. Cell Rep. 10, 1055–1065 (2015).
Cardoso, S. R. et al. Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia. Leukemia 30, 2083–2086 (2016).
Li, R., Sobreira, N., Witmer, P. D., Pratz, K. W. & Braunstein, E. M. Two novel germline DDX41 mutations in a family with inherited myelodysplasia/acute myeloid leukemia. Haematologica 101, e228–e231 (2016).
Lewinsohn, M. et al. Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood 127, 1017–1023 (2016).
Sebert, M. et al. Germline DDX41 mutations define a significant entity within adult MDS/AML patients. Blood 134, 1441–1444 (2019).
Quesada, A. E. et al. DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease. Am. J. Hematol. 94, 757–766 (2019).
Polprasert, C. et al. Novel DDX41 variants in Thai patients with myeloid neoplasms. Int. J. Hematol. 111, 241–246 (2020).
Takeda, J. et al. Genetic predispositions to myeloid neoplasms caused by germline DDX41 mutations. Blood 126, 2843–2843 (2015).
Inoue, D., Bradley, R. K. & Abdel-Wahab, O. Spliceosomal gene mutations in myelodysplasia: molecular links to clonal abnormalities of hematopoiesis. Genes Dev. 30, 989–1001 (2016).
Kadono, M. et al. Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia. Exp. Hematol. 44, 745–754.e4 (2016).
Chen, D. H. et al. Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L. Am. J. Hum. Genet. 98, 1146–1158 (2016).
Buonocore, F. et al. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J. Clin. Invest. 127, 1700–1713 (2017).
Schwartz, J. R. et al. The genomic landscape of pediatric myelodysplastic syndromes. Nat. Commun. 8, 1557 (2017). This study is the first to comprehensively profile the genomic landscape of paediatric MDS and describes germline mutations in SAMD9 or SAMD9L in nearly 20% of cases.
Bluteau, O. et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood 131, 717–732 (2018).
Nagata, Y. et al. Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes. Blood 132, 2309–2313 (2018).
Nagamachi, A. et al. Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. Cancer Cell 24, 305–317 (2013).
Liu, J. & McFadden, G. SAMD9 is an innate antiviral host factor with stress response properties that can be antagonized by poxviruses. J. Virol. 89, 1925–1931 (2015).
Nounamo, B. et al. An interaction domain in human SAMD9 is essential for myxoma virus host-range determinant M062 antagonism of host anti-viral function. Virology 503, 94–102 (2017).
Sivan, G., Ormanoglu, P., Buehler, E. C., Martin, S. E. & Moss, B. Identification of restriction factors by human genome-wide RNA interference screening of viral host range mutants exemplified by discovery of SAMD9 and WDR6 as inhibitors of the vaccinia virus K1L–C7L– mutant. mBio 6, e01122 (2015).
Meng, X. et al. A paralogous pair of mammalian host restriction factors form a critical host barrier against poxvirus infection. PLoS Pathog. 14, e1006884 (2018).
Mekhedov, S. L., Makarova, K. S. & Koonin, E. V. The complex domain architecture of SAMD9 family proteins, predicted STAND-like NTPases, suggests new links to inflammation and apoptosis. Biol. Direct 12, 13 (2017).
Wong, J. C. et al. Functional evidence implicating chromosome 7q22 haploinsufficiency in myelodysplastic syndrome pathogenesis. eLife 4, e07839 (2015).
Honda, H., Nagamachi, A. & Inaba, T. -7/7q- syndrome in myeloid-lineage hematopoietic malignancies: attempts to understand this complex disease entity. Oncogene 34, 2413–2425 (2015).
de Jesus, A. A. et al. Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. J. Clin. Invest. 130, 1669–1682 (2020).
Ripperger, T. et al. MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies. Haematologica 103, e55–e58 (2018).
Rio-Machin, A. et al. The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants. Nat. Commun. 11, 1044 (2020).
Bluteau, D. et al. Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. J. Clin. Invest. 124, 580–591 (2014).
Al Daama, S. A. et al. A missense mutation in ANKRD26 segregates with thrombocytopenia. Blood 122, 461–462 (2013).
Noris, P. et al. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood 117, 6673–6680 (2011).
Pippucci, T. 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. 88, 115–120 (2011).
Perez Botero, J. et al. ASXL1 mutated chronic myelomonocytic leukemia in a patient with familial thrombocytopenia secondary to germline mutation in ANKRD26. Blood Cancer J. 5, e315 (2015).
Sanders, M. A. et al. MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML. Blood 132, 1526–1534 (2018).
Ward, A. F., Braun, B. S. & Shannon, K. M. Targeting oncogenic Ras signaling in hematologic malignancies. Blood 120, 3397–3406 (2012).
Arico, M., Biondi, A. & Pui, C. H. Juvenile myelomonocytic leukemia. Blood 90, 479–488 (1997).
Niemeyer, C. M. & Kratz, C. P. Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia: molecular classification and treatment options. Br. J. Haematol. 140, 610–624 (2008).
Flotho, C. et al. Genotype–phenotype correlation in cases of juvenile myelomonocytic leukemia with clonal RAS mutations. Blood 111, 966–967 (2008).
Chang, T. Y., Dvorak, C. C. & Loh, M. L. Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia. Blood 124, 2487–2497 (2014).
Stiller, C. A., Chessells, J. M. & Fitchett, M. Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br. J. Cancer 70, 969–972 (1994).
Shannon, K. M. et al. Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N. Engl. J. Med. 330, 597–601 (1994).
Niemeyer, C. M. JMML genomics and decisions. Hematol. Am. Soc. Hematol Educ. Program. 2018, 307–312 (2018).
Niemeyer, C. M. et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat. Genet. 42, 794–800 (2010). This genomic and clinical analysis of patients with germline CBL mutations demonstrates a propensity for spontaneous resolution of haematopoietic abnormalities with prolonged risk for vascular and developmental complications.
Loh, M. L. et al. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 114, 1859–1863 (2009).
Strullu, M. et al. Juvenile myelomonocytic leukaemia and Noonan syndrome. J. Med. Genet. 51, 689–697 (2014).
Kratz, C. P. et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 106, 2183–2185 (2005).
Cave, H. et al. Acute lymphoblastic leukemia in the context of RASopathies. Eur. J. Med. Genet. 59, 173–178 (2016).
Cave, H. et al. Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia. Eur. J. Hum. Genet. 24, 1124–1131 (2016).
Flex, E. et al. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum. Mol. Genet. 23, 4315–4327 (2014).
Roberts, A. E. et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat. Genet. 39, 70–74 (2007).
Kratz, C. P., Rapisuwon, S., Reed, H., Hasle, H. & Rosenberg, P. S. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am. J. Med. Genet. 157, 83–89 (2011).
Stieglitz, E. et al. The genomic landscape of juvenile myelomonocytic leukemia. Nat. Genet. 47, 1326–1333 (2015). This paper genomically characterizes serial samples from patients with JMML, including diagnosis, relapse and transformation to AML, and identifies recurrent mutations in genes involved in signal transduction, splicing, PRC2 and transcription.
Caye, A. et al. Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat. Genet. 47, 1334–1340 (2015).
Murakami, N. et al. Integrated molecular profiling of juvenile myelomonocytic leukemia. Blood 131, 1576–1586 (2018).
Stieglitz, E. et al. Subclonal mutations in SETBP1 confer a poor prognosis in juvenile myelomonocytic leukemia. Blood 125, 516–524 (2015).
Stieglitz, E. et al. Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia. Nat. Commun. 8, 2127 (2017).
Lipka, D. B. et al. RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia. Nat. Commun. 8, 2126 (2017).
Hitzler, J. K. & Zipursky, A. Origins of leukaemia in children with down syndrome. Nat. Rev. Cancer 5, 11–20 (2005).
Mullighan, C. G. et al. Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat. Genet. 41, 1243–1246 (2009).
Lange, B. J. et al. Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children’s Cancer Group Studies 2861 and 2891. Blood 91, 608–615 (1998).
Rainis, L. et al. Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 102, 981–986 (2003).
Wechsler, J. et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat. Genet. 32, 148–152 (2002).
Li, Z. et al. Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat. Genet. 37, 613–619 (2005).
Yoshida, K. et al. The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat. Genet. 45, 1293–1299 (2013).
Mateos, M. K., Barbaric, D., Byatt, S. A., Sutton, R. & Marshall, G. M. Down syndrome and leukemia: insights into leukemogenesis and translational targets. Transl. Pediatr. 4, 76–92 (2015).
Landgren, O. et al. Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24,577 first-degree relatives of 11,039 patients with myeloproliferative neoplasms in Sweden. Blood 112, 2199–2204 (2008).
Jones, A. V. et al. The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms. Blood 115, 4517–4523 (2010).
Jones, A. V. et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat. Genet. 41, 446–449 (2009).
Kilpivaara, O. et al. A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms. Nat. Genet. 41, 455–459 (2009).
Olcaydu, D. et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat. Genet. 41, 450–454 (2009).
Andrikovics, H. et al. JAK2 46/1 haplotype analysis in myeloproliferative neoplasms and acute myeloid leukemia. Leukemia 24, 1809–1813 (2010).
Trifa, A. P. et al. MECOM, HBS1L-MYB, THRB-RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: a study on 939 patients. Am. J. Hematol. 93, 100–106 (2018).
Tapper, W. et al. Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. Nat. Commun. 6, 6691 (2015).
Harutyunyan, A. S. et al. Germline RBBP6 mutations in familial myeloproliferative neoplasms. Blood 127, 362–365 (2016).
Chen, Y. et al. The polymorphisms in LNK gene correlated to the clinical type of myeloproliferative neoplasms. PLoS ONE 11, e0154183 (2016).
Rumi, E. et al. LNK mutations in familial myeloproliferative neoplasms. Blood 128, 144–145 (2016).
Saliba, J. et al. Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. Nat. Genet. 47, 1131–1140 (2015).
Izraeli, S. The acute lymphoblastic leukemia of Down syndrome—genetics and pathogenesis. Eur. J. Med. Genet. 59, 158–161 (2016).
Pastorczak, A., Szczepanski, T. & Mlynarski, W. Clinical course and therapeutic implications for lymphoid malignancies in Nijmegen breakage syndrome. Eur. J. Med. Genet. 59, 126–132 (2016).
Schutte, P. et al. Preexisting conditions in pediatric ALL patients: spectrum, frequency and clinical impact. Eur. J. Med. Genet. 59, 143–151 (2016).
Harrison, C. J. & Schwab, C. Constitutional abnormalities of chromosome 21 predispose to iAMP21-acute lymphoblastic leukaemia. Eur. J. Med. Genet. 59, 162–165 (2016).
Trevino, L. R. et al. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat. Genet. 41, 1001–1005 (2009). This study is one of the first to demonstrate the utility of GWAS to identify susceptibility loci in B-ALL.
Vijayakrishnan, J. et al. Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk. Nat. Commun. 10, 5348 (2019).
Karol, S. E. et al. Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia. Leukemia 31, 1325–1332 (2017).
Yang, J. J. et al. Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat. Genet. 43, 237–241 (2011).
Holmfeldt, L. et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat. Genet. 45, 242–252 (2013). This paper presents genomic analysis of hypodiploid ALL, showing constellations of genomic alterations in low hypodiploid and near haploid ALL and near-universal TP53 mutation in low hypodiploid ALL, approximately half of which are germline in paediatric, but not adult, low hypodiploid ALL.
Noetzli, L. et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat. Genet. 47, 535–538 (2015). This paper is one of the initial studies documenting the syndrome of germline ETV6 mutation, thrombocytopenia and ALL.
Zhang, M. Y. et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat. Genet. 47, 180–185 (2015).
Jarviaho, T. et al. Predisposition to childhood acute lymphoblastic leukemia caused by a constitutional translocation disrupting ETV6. Blood Adv. 3, 2722–2731 (2019).
Rampersaud, E. et al. Germline deletion of ETV6 in familial acute lymphoblastic leukemia. Blood Adv. 3, 1039–1046 (2019).
Szczepanski, T. et al. Late recurrence of childhood T-cell acute lymphoblastic leukemia frequently represents a second leukemia rather than a relapse: first evidence for genetic predisposition. J. Clin. Oncol. 29, 1643–1649 (2011). This study focuses on the genomics of relapse in T-ALL, identifying a case with germline deletions of LMO2, and demonstrates that relapse is due to propagation of a second primary leukaemia.
Waanders, E. et al. Mutational landscape and patterns of clonal evolution in relapsed pediatric acute lymphoblastic leukemia. Blood Cancer Discov. 1, 96–111 (2020).
Qian, M. et al. TP53 germline variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children. J. Clin. Oncol. 36, 591–599 (2018).
Papaemmanuil, E. et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat. Genet. 41, 1006–1010 (2009).
Urayama, K. Y. et al. Regional evaluation of childhood acute lymphoblastic leukemia genetic susceptibility loci among Japanese. Sci. Rep. 8, 789 (2018).
Xu, H. et al. Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations. J. Natl Cancer Inst. 105, 733–742 (2013).
Migliorini, G. et al. Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood 122, 3298–3307 (2013).
Sherborne, A. L. et al. Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk. Nat. Genet. 42, 492–494 (2010).
Hungate, E. A. et al. A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology. Nat. Commun. 7, 10635 (2016).
Vijayakrishnan, J. & Houlston, R. S. Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Haematologica 95, 1405–1414 (2010).
Wiemels, J. L. et al. GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21. Nat. Commun. 9, 286 (2018).
Ellinghaus, E. et al. Identification of germline susceptibility loci in ETV6–RUNX1-rearranged childhood acute lymphoblastic leukemia. Leukemia 26, 902–909 (2012).
Jain, N. et al. GATA3 rs3824662A allele is overrepresented in adult patients with Ph-like ALL, especially in patients with CRLF2 abnormalities. Blood 130, 1430–1430 (2017).
Qian, M. et al. Genome-wide association study of susceptibility loci for T-cell acute lymphoblastic leukemia in children. J. Natl Cancer Inst. 111, 1350–1357 (2019).
Liu, Y. et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat. Genet. 49, 1211–1218 (2017).
Somasundaram, R., Prasad, M. A., Ungerback, J. & Sigvardsson, M. Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia. Blood 126, 144–152 (2015).
Roberts, K. G. & Mullighan, C. G. The biology of B-progenitor acute lymphoblastic leukemia. Cold Spring Harb. Perspect. Med. 10, a034835 (2020).
Yang, H. et al. Non-coding germline GATA3 variants alter chromatin topology and contribute to pathogenesis of acute lymphoblastic leukemia. Preprint at bioRxiv https://doi.org/10.1101/2020.02.23.961672 (2020).
Auer, F. et al. Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A. Leukemia 28, 1136–1138 (2014).
Nutt, S. L., Heavey, B., Rolink, A. G. & Busslinger, M. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 401, 556–562 (1999).
Mullighan, C. G. et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446, 758–764 (2007).
Kuiper, R. P. et al. High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia 21, 1258–1266 (2007).
An, Q. et al. Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer. Proc. Natl Acad. Sci. USA 105, 17050–17054 (2008).
Bousquet, M. et al. A novel PAX5–ELN fusion protein identified in B-cell acute lymphoblastic leukemia acts as a dominant negative on wild-type PAX5. Blood 109, 3417–3423 (2007).
Cazzaniga, G. et al. The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case. Cancer Res. 61, 4666–4670 (2001).
Coyaud, E. et al. Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogenetique Hematologique study. Blood 115, 3089–3097 (2010).
Kawamata, N. et al. Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray. Blood 111, 776–784 (2008).
Nebral, K. et al. Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia. Leukemia 23, 134–143 (2009).
Strehl, S., Konig, M., Dworzak, M. N., Kalwak, K. & Haas, O. A. PAX5/ETV6 fusion defines cytogenetic entity dic(9;12)(p13;p13). Leukemia 17, 1121–1123 (2003).
Schwab, C. et al. Intragenic amplification of PAX5: a novel subgroup in B-cell precursor acute lymphoblastic leukemia? Blood Adv. 1, 1473–1477 (2017).
Gu, Z. et al. PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nat. Genet. 51, 296–307 (2019). This paper presents a large-scale genomic analysis of B-ALL identifying new subtypes driven by diverse PAX5 alterations, including a single mutation defining one subgroup (PAX5P80R).
Eberhard, D., Jimenez, G., Heavey, B. & Busslinger, M. Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family. EMBO J. 19, 2292–2303 (2000).
Dang, J. et al. Pax5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia. Blood 125, 3609–3617 (2015).
Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).
Guha, T. & Malkin, D. Inherited TP53 mutations and the Li–Fraumeni syndrome. Cold Spring Harb. Perspect. Med. 7, a026187 (2017).
Zebisch, A. et al. Acute myeloid leukemia with TP53 germ line mutations. Blood 128, 2270–2272 (2016).
Link, D. C. et al. Identification of a novel TP53 cancer susceptibility mutation through whole-genome sequencing of a patient with therapy-related AML. JAMA 305, 1568–1576 (2011).
Harrison, C. J. et al. Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia. Br. J. Haematol. 125, 552–559 (2004).
Groeneveld-Krentz, S. et al. Aneuploidy in children with relapsed B-cell precursor acute lymphoblastic leukaemia: clinical importance of detecting a hypodiploid origin of relapse. Br. J. Haematol. 185, 266–283 (2019).
Muhlbacher, V. et al. Acute lymphoblastic leukemia with low hypodiploid/near triploid karyotype is a specific clinical entity and exhibits a very high TP53 mutation frequency of 93%. Genes Chromosomes Cancer 53, 524–536 (2014).
Swaminathan, M. et al. Hematologic malignancies and Li–Fraumeni syndrome. Cold Spring Harb. Mol. Case Stud. 5, a003210 (2019).
Chen, Q. et al. Multiple functions of Ikaros in hematological malignancies, solid tumor and autoimmune diseases. Gene 684, 47–52 (2019).
Georgopoulos, K. et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell 79, 143–156 (1994).
Mullighan, C. G. et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453, 110–114 (2008).
Mullighan, C. G. et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N. Engl. J. Med. 360, 470–480 (2009).
Den Boer, M. L. et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 10, 125–134 (2009).
Zhang, J. et al. Deregulation of DUX4 and ERG in acute lymphoblastic leukemia. Nat. Genet. 48, 1481–1489 (2016).
Martinelli, G. et al. IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: a GIMEMA AL WP report. J. Clin. Oncol. 27, 5202–5207 (2009).
van der Veer, A. et al. IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL. Blood 123, 1691–1698 (2014).
Zaliova, M. et al. ERG deletion is associated with CD2 and attenuates the negative impact of IKZF1 deletion in childhood acute lymphoblastic leukemia. Leukemia 28, 182–185 (2014).
Dorge, P. et al. IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica 98, 428–432 (2013).
Slayton, W. B. et al. Dasatinib plus intensive chemotherapy in children, adolescents, and young adults with philadelphia chromosome-positive acute lymphoblastic leukemia: results of Children’s Oncology Group trial AALL0622. J. Clin. Oncol. 36, 2306–2314 (2018).
Li, J. F. et al. Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. Proc. Natl Acad. Sci. USA 115, E11711–e11720 (2018).
Iacobucci, I. et al. Expression of spliced oncogenic Ikaros isoforms in Philadelphia-positive acute lymphoblastic leukemia patients treated with tyrosine kinase inhibitors: implications for a new mechanism of resistance. Blood 112, 3847–3855 (2008).
Churchman, M. L. et al. Efficacy of retinoids in IKZF1-mutated BCR-ABL1 acute lymphoblastic leukemia. Cancer Cell 28, 343–356 (2015).
Joshi, I. et al. Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia. Nat. Immunol. 15, 294–304 (2014).
Virely, C. et al. Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemia. Leukemia 24, 1200–1204 (2010).
Boutboul, D. et al. Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J. Clin. Invest. 128, 3071–3087 (2018).
Kuehn, H. S. et al. Loss of B cells in patients with heterozygous mutations in IKAROS. N. Engl. J. Med. 374, 1032–1043 (2016). This paper identifies IKZF1 germline mutations in the region encoding the N-terminal zinc finger as a cause of B-lineage immunodeficiency.
Yoshida, N. et al. Germline IKAROS mutation associated with primary immunodeficiency that progressed to T-cell acute lymphoblastic leukemia. Leukemia 31, 1221–1223 (2017).
Hoshino, A. et al. Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations. J. Allergy Clin. Immunol. 140, 223–231 (2017).
Lentaigne, C. et al. Germline mutations in the transcription factor IKZF5 cause thrombocytopenia. Blood 134, 2070–2081 (2019).
Hock, H. & Shimamura, A. ETV6 in hematopoiesis and leukemia predisposition. Semin. Hematol. 54, 98–104 (2017).
Shurtleff, S. A. et al. TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia 9, 1985–1989 (1995).
Raynaud, S. et al. The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia. Blood 87, 2891–2899 (1996).
Papaemmanuil, E. et al. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6–RUNX1 acute lymphoblastic leukemia. Nat. Genet. 46, 116–125 (2014).
Di Paola, J. & Porter, C. C. ETV6-related thrombocytopenia and leukemia predisposition. Blood 134, 663–667 (2019).
Melazzini, F. et al. Clinical and pathogenic features of ETV6-related thrombocytopenia with predisposition to acute lymphoblastic leukemia. Haematologica 101, 1333–1342 (2016).
Paulsson, K. et al. Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Proc. Natl Acad. Sci. USA 107, 21719–21724 (2010).
Nishii, R. et al. Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia. Blood https://doi.org/10.1182/blood.2020006164 (2020).
Poggi, M. et al. Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors. Haematologica 102, 282–294 (2017).
Karastaneva, A. et al. Novel phenotypes observed in patients with ETV6-linked leukaemia/familial thrombocytopenia syndrome and a biallelic ARID5B risk allele as leukaemogenic cofactor. J. Med. Genet. 57, 427–433 (2020).
Bersenev, A., Wu, C., Balcerek, J. & Tong, W. Lnk controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2. J. Clin. Invest. 118, 2832–2844 (2008).
Roberts, K. G. et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N. Engl. J. Med. 371, 1005–1015 (2014).
Roberts, K. G. et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 22, 153–166 (2012).
Perez-Garcia, A. et al. Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood 122, 2425–2432 (2013).
Lin, M. et al. JAK2 p.G571S in B-cell precursor acute lymphoblastic leukemia: a synergizing germline susceptibility. Leukemia 33, 2331–2335 (2019).
Waanders, E. et al. Germline activating TYK2 mutations in pediatric patients with two primary acute lymphoblastic leukemia occurrences. Leukemia 31, 821–828 (2017).
Sanda, T. et al. TYK2–STAT1–BCL2 pathway dependence in T-cell acute lymphoblastic leukemia. Cancer Discov. 3, 564–577 (2013).
Mullighan, C. G. et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235–239 (2011).
Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471, 189–195 (2011).
de Smith, A. J. et al. Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children. Genes Chromosomes Cancer 58, 723–730 (2019).
Winer, P. et al. Germline variants in predisposition genes in children with Down syndrome and acute lymphoblastic leukemia. Blood Adv. 4, 672–675 (2020).
Pouliot, G. P. et al. Fanconi–BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia. PLoS ONE 14, e0221288 (2019).
Wilson, C. L. et al. Estimated number of adult survivors of childhood cancer in United States with cancer-predisposing germline variants. Pediatr. Blood Cancer 67, e28047 (2020).
Oberg, J. A. et al. Implementation of next generation sequencing into pediatric hematology–oncology practice: moving beyond actionable alterations. Genome Med. 8, 133 (2016).
Sud, A. et al. Analysis of 153 115 patients with hematological malignancies refines the spectrum of familial risk. Blood 134, 960–969 (2019).
Diets, I. J. et al. High yield of pathogenic germline mutations causative or likely causative of the cancer phenotype in selected children with cancer. Clin. Cancer Res. 24, 1594–1603 (2018).
Pastor, S. et al. Optical mapping of the 22q11.2DS region reveals complex repeat structures and preferred locations for non-allelic homologous recombination (NAHR). Sci. Rep. 10, 12235 (2020).
Jenko Bizjan, B. et al. Challenges in identifying large germline structural variants for clinical use by long read sequencing. Comput. Struct. Biotechnol. J. 18, 83–92 (2020).
Ritter, D. I. et al. A case for expert curation: an overview of cancer curation in the Clinical Genome Resource (ClinGen). Cold Spring Harb. Mol. Case Stud. 5, a004739 (2019).
Luo, X. et al. ClinGen myeloid malignancy variant curation expert panel recommendations for germline RUNX1 variants. Blood Adv. 3, 2962–2979 (2019).
Mullighan, C. G. The ASH Agenda for Hematology Research: a roadmap for advancing scientific discovery and cures for hematologic diseases. Blood Adv. 2, 2430–2432 (2018).
Rehm, H. L. et al. ClinGen — the Clinical Genome Resource. N. Engl. J. Med. 372, 2235–2242 (2015).
Findlay, G. M. et al. Accurate classification of BRCA1 variants with saturation genome editing. Nature 562, 217–222 (2018).
Boettcher, S. et al. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science 365, 599–604 (2019).
Wu, D. et al. How I curate: applying American Society of Hematology–Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies. Haematologica 105, 870–887 (2020).
Hahn, C. N. et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat. Genet. 43, 1012–1017 (2011).
Hirabayashi, S., Wlodarski, M. W., Kozyra, E. & Niemeyer, C. M. Heterogeneity of GATA2-related myeloid neoplasms. Int. J. Hematol. 106, 175–182 (2017).
Dokal, I. Dyskeratosis congenita in all its forms. Br. J. Haematol. 110, 768–779 (2000).
Savage, S. A. & Dufour, C. Classical inherited bone marrow failure syndromes with high risk for myelodysplastic syndrome and acute myelogenous leukemia. Semin. Hematol. 54, 105–114 (2017).
Alter, B. P. et al. Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br. J. Haematol. 150, 179–188 (2010).
Rusch, M. et al. Clinical cancer genomic profiling by three-platform sequencing of whole genome, whole exome and transcriptome. Nat. Commun. 9, 3962 (2018).
Howard Sharp, K. M. et al. Factors associated with declining to participate in a pediatric oncology next generation sequencing study. JCO Precis. Oncol. 4, 202–211 (2020).
Berger, G. et al. Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation. Leukemia 31, 520–522 (2017).
Kobayashi, S. et al. Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation. Leukemia 31, 1020–1022 (2017).
Galera, P. et al. Donor-derived MDS/AML in families with germline GATA2 mutation. Blood 132, 1994–1998 (2018).
Acknowledgements
The authors thank I. Iacobucci for assistance with figure preparation. The authors are supported by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital, the St. Jude Comprehensive Cancer Center (Core Grant CA021765), the National Heart, Lung, and Blood Institute (NHLBI) (R01 HL144653 to J.M.K.), the Edward P. Evans Foundation (to J.M.K.), the National Cancer Institute (NCI) (R35 CA197695 to C.G.M.), the Henry Schueler 19 Foundation (to C.G.M.) and a St. Baldrick’s Foundation Robert J. Arceci Innovation Award (to C.G.M.).
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C.G.M. has received research funding from Loxo Oncology, Pfizer and AbbVie; has received speaking and travel fees from Amgen; holds stock in Amgen; and has been compensated for advisory board participation for Illumina. J.M.K. declares no competing interests.
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ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/
Online Mendelian Inheritance in Man (OMIM): https://www.omim.org/
RefSeq: https://www.ncbi.nlm.nih.gov/refseq/
St Jude Cloud Visualization Community: https://viz.stjude.cloud/stjude/visualization/pax5-driven-subtypes-of-b-progenitor-acute-lymphoblastic-leukemia-genomepaint
Glossary
- Clonal haematopoiesis
-
The expansion of a clonal population of haematopoietic cells marked by somatic mutations.
- Cytopenic phase
-
A period marked by a decrease in peripheral blood cell counts (anaemia, red blood cells; thrombocytopenia, platelets; leukopenia, white blood cells).
- Monocytopenia
-
A decrease in monocytes.
- Pulmonary alveolar proteinosis
-
A lung disease characterized by a build-up of proteins and lipids in the functional units of the lung (alveoli) that is part of MonoMac syndrome, which results from GATA2 germline mutations.
- Sensorineural deafness
-
A form of hearing loss that results from damage to the inner ear or auditory nerve that is part of Emberger syndrome, which results from GATA2 germline mutations.
- Thrombocytopenia 2
-
An autosomal dominant syndrome resulting from germline mutations in ANKRD26 that is characterized by lifelong mild-to-moderate thrombocytopenia and an increase in the risk for myeloid malignancies.
- Philadelphia chromosome-like ALL
-
A group of B lymphoblastic leukaemias that have a global expression profile similar to BCR–ABL1-positive (Ph+) acute lymphoblastic leukaemia (ALL) but have alterations in other kinase signalling and cytokine receptor pathways.
- Ataxia telangiectasia
-
An autosomal recessive condition caused by mutations in the ATM gene. This syndrome is characterized by immunodeficiency, decreased DNA damage repair and neurological abnormalities.
- Nijmegen breakage syndrome
-
An autosomal recessive disorder that leads to chromosomal instability and is clinically characterized by microcephaly, growth retardation, immunodeficiency and predisposition to cancer.
- Robertsonian translocation
-
A non-reciprocal chromosomal translocation in which the long arms of two distinct acrocentric chromosomes become fused and share a single centromere.
- Ring chromosome
-
An abnormal chromosome in which the ends of a single chromosome fuse to form a ring.
- Li–Fraumeni syndrome
-
An autosomal dominant condition caused by an inherited mutation in TP53 that renders humans highly susceptible to numerous cancers, including breast cancer, leukaemia and sarcoma.
- BCR–ABL1-positive (Ph+) B-ALL
-
A class of B cell acute lymphoblastic leukaemia (B-ALL) haematopoietic disorders driven by the BCR–ABL1 fusion oncoprotein.
- Optical mapping
-
An approach to genome assembly in which DNA molecules are fluorescently labelled and imaged to construct maps.
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Klco, J.M., Mullighan, C.G. Advances in germline predisposition to acute leukaemias and myeloid neoplasms. Nat Rev Cancer 21, 122–137 (2021). https://doi.org/10.1038/s41568-020-00315-z
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DOI: https://doi.org/10.1038/s41568-020-00315-z
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