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Editorials
4. Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005-1015.
5. Reshmi SC, Harvey RC, Roberts KG, et al. Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group. Blood. 2017;129(25):3352-3361.
6. Roberts KG, Gu Z, Payne-Turner D, et al. High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults. J Clin Oncol. 2017;35(4):394-401.
7. Weston BW, Hayden MA, Roberts KG, et al. Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia. J Clin Oncol. 2013;31(25):e413-416.
8. Tanasi I, Ba I, Sirvent N, et al. Efficacy of tyrosine kinase inhibitors in Ph-like acute lymphoblastic leukemia harboring ABL-class rearrangements. Blood. 2019;134(16):1351-1355.
9. Cario G, Leoni V, Conter V, et al. Relapses and treatment-related events contributed equally to poor prognosis in children with ABL- class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols. Haematologica 2020;105(7): 1887-1894.
10. Schwab C, Ryan SL, Chilton L, et al. EBF1-PDGFRB fusion in pedi- atric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): genetic profile and clinical implications. Blood. 2016;127(18):2214- 2218.
11. Conter V, Bartram CR, Valsecchi MG, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 2010;115 (16):3206-3214.
12. Arico M, Valsecchi MG, Camitta B, et al. Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblas- tic leukemia. N Engl J Med. 2000;342(14):998-1006.
13. Schultz KR, Carroll A, Heerema NA, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lym- phoblastic leukemia: Children's Oncology Group study AALL0031.
Leukemia. 2014;28(7):1467-1471.
14. Biondi A, Gandemer V, De Lorenzo P, et al. Imatinib treatment of
paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (EsPhALL2010): a prospective, intergroup, open-label, sin- gle-arm clinical trial. Lancet Haematol. 2018;5(12):e641-e652.
15. Slayton WB, Schultz KR, Kairalla JA, 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. 2018;36(22):2306-2314.
16. Roberts KG, Pei D, Campana D, et al. Outcomes of children with BCR-ABL1-like acute lymphoblastic leukemia treated with risk- directed therapy based on the levels of minimal residual disease. J Clin Oncol. 2014;32(27):3012-3020.
17. Testi AM, Attarbaschi A, Valsecchi MG, et al. Outcome of adoles- cent patients with acute lymphoblastic leukaemia aged 10-14 years as compared with those aged 15-17 years: Long-term results of 1094 patients of the AIEOP-BFM ALL 2000 study. Eur J Cancer. 2019;122:61-71.
18. Martinelli G, Boissel N, Chevallier P, et al. Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. J Clin Oncol. 2017;35(16):1795-1802.
19. Chiaretti S, Bassan R, Vitale A, et al. Dasatinib-Blinatumomab Combination for the Front-Line Treatment of Adult Ph+ ALL Patients. Updated Results of the Gimema LAL2116 D-Alba Trial. Blood. 2019;134(Suppl 1):740.
20. Jabbour E, Roberts KG, Sasaki K, et al. Inotuzumab Ozogamicin May Overcome the Impact of Philadelphia Chromosome-like Phenotype in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia. Blood. 2019;134(Suppl_1):1641.
21. Roberts KG, Reshmi SC, Harvey RC, et al. Genomic and Outcome Analyses of Ph-like ALL in NCI Standard-risk Patients: A Report from the Children’s Oncology Group. Blood. 2018;132:815-824.
NUP98 and KMT2A: usually the bride rather than the bridesmaid Alexandre Fagnan1,2,3 and Thomas Mercher1,2,3.4
1INSERM U1170, Gustave Roussy Institute, Villejuif; 2Université Paris Diderot, Paris; 3Equipe labellisée Ligue Nationale Contre le Cancer, Paris and 4Université Paris-Saclay, Villejuif, France
E-mail: THOMAS MERCHER - thomas.mercher@inserm.fr doi:10.3324/haematol.2020.253476
In human hematopoietic malignancies, KMT2A and NUP98 are each independently targeted by numerous chromosomal alterations leading to the expression of fusion oncogenes. In this issue of Haematologica, Fisher and colleagues from J. Schwaller's team report the func- tional study and creation of an in vivo model1 for a unique fusion between these two genes2 showing that leukemia development by NUP98-KMT2A is not associated with classical KMT2A fusion mechanisms.
KMT2A (a.k.a. MLL) is a large protein of almost 4,000 amino acids that is processed by the endopeptidase Taspase1. It interacts with numerous proteins and assem- bles into large protein complexes (Figure 1). The functions of KMT2A include writing the H3K4me3 chromatin mark characteristic of active promoter regions through its C- terminal SET domain. In both lymphoid and myeloid malignancies, KMT2A is targeted by numerous chromo- somal alterations resulting in the expression of fusion oncogenes with over 80 different partners in toto (https://mitelmandatabase.isb-cgc.org/). Experimental mod- els have demonstrated that several fusions containing the N-terminal portion of KMT2A and various partners [here
termed KMT2A-X, where X is frequently AFF1, MLLT3, MLLT10 or MLLT1 in acute lymphoid leukemia patients, and MLLT3, MLLT10, MLLT1 or ELL in patients with acute myeloid leukemia (AML)] are important for disease development and maintenance.3,4
It has long been recognized that KMT2A-X fusions acti- vate transcription of different HOX genes (e.g. HOXC8, HOXA7, HOXA9, and HOXA10) and are associated with high expression of the HOX cofactor MEIS1. At the molecular level, at least two distinct mechanisms have been involved in KMT2A-X leukemogenic properties and the deregulated expression of KMT2A-X target genes (Figure 1). On the one hand, the first 145 N-terminal amino acids of KMT2A interact with MEN1 and LEDGF to bind KMT2A target genes.5 On the other hand, most fusion partners of KMT2A belong to the transcription elongation machinery leading to the active recruitment of various factors including (i) the P-TEFb complex (com- prising CDK9), which phosphorylates RNA polymerase II; and (ii) the histone methyltransferases DOT1L and NSD1, which catalyze H3K79me3 and H3K36me2 marks deposited in the body of actively transcribed genes. This
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