Mechanisms Associated with T(7;12) Acute Myeloid Leukaemia: from Genetics to Potential Treatment Targets

Overview

Journal Biosci Rep

Specialty Cell Biology

Date 2023 Jan 9

PMID 36622782

Authors

Denise Ragusa

Liza Dijkhuis

Cristina Pina

Sabrina Tosi

Affiliations

Soon will be listed here.

Abstract

Acute myeloid leukaemia (AML), typically a disease of elderly adults, affects 8 children per million each year, with the highest paediatric incidence in infants aged 0-2 of 18 per million. Recurrent cytogenetic abnormalities contribute to leukaemia pathogenesis and are an important determinant of leukaemia classification. The t(7;12)(q36;p13) translocation is a high-risk AML subtype exclusively associated with infants and represents the second most common abnormality in this age group. Mechanisms of t(7;12) leukaemogenesis remain poorly understood. The translocation relocates the entire MNX1 gene within the ETV6 locus, but a fusion transcript is present in only half of the patients and its significance is unclear. Instead, research has focused on ectopic MNX1 expression, a defining feature of t(7;12) leukaemia, which has nevertheless failed to produce transformation in conventional disease models. Recently, advances in genome editing technologies have made it possible to recreate the t(7;12) rearrangement at the chromosomal level. Together with recent studies of MNX1 involvement using murine in vivo, in vitro, and organoid-based leukaemia models, specific investigation on the biology of t(7;12) can provide new insights into this AML subtype. In this review, we provide a comprehensive up-to-date analysis of the biological features of t(7;12), and discuss recent advances in mechanistic understanding of the disease which may deliver much-needed therapeutic opportunities to a leukaemia of notoriously poor prognosis.

Citing Articles

Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13).

Weichenhan D, Riedel A, Sollier E, Toprak U, Hey J, Breuer K Blood Adv. 2024; 8(19):5100-5111.

PMID: 39121370 PMC: 11460460. DOI: 10.1182/bloodadvances.2023012161.

Acute myeloid leukemia with rare recurring translocations-an overview of the entities included in the international consensus classification.

Rorvik S, Torkildsen S, Bruserud O, Anderson Tvedt T Ann Hematol. 2024; 103(4):1103-1119.

PMID: 38443661 PMC: 10940453. DOI: 10.1007/s00277-024-05680-5.

Panel-based RNA fusion sequencing improves diagnostics of pediatric acute myeloid leukemia.

Hoffmeister L, Suttorp J, Walter C, Antoniou E, Behrens Y, Gohring G Leukemia. 2023; 38(3):538-544.

PMID: 38086945 PMC: 10912021. DOI: 10.1038/s41375-023-02102-9.

First mouse model of infant acute myeloid leukemia with t(7;12)(q36;p17).

Jevtic Z, Schwaller J Haematologica. 2023; 109(3):712-714.

PMID: 37584296 PMC: 10905090. DOI: 10.3324/haematol.2023.283659.

References

Namayandeh S, Khazaei Z, Najafi M, Goodarzi E, Moslem A . GLOBAL Leukemia in Children 0-14 Statistics 2018, Incidence and Mortality and Human Development Index (HDI): GLOBOCAN Sources and Methods. Asian Pac J Cancer Prev. 2020; 21(5):1487-1494. PMC: 7541866. DOI: 10.31557/APJCP.2020.21.5.1487. View

Federico C, Owoka T, Ragusa D, Sturiale V, Caponnetto D, Leotta C . Deletions of Chromosome 7q Affect Nuclear Organization and Gene Expression in Hematological Disorders. Cancers (Basel). 2019; 11(4). PMC: 6521283. DOI: 10.3390/cancers11040585. View

Rack K, van den Berg E, Haferlach C, Beverloo H, Costa D, Espinet B . European recommendations and quality assurance for cytogenomic analysis of haematological neoplasms. Leukemia. 2019; 33(8):1851-1867. PMC: 6756035. DOI: 10.1038/s41375-019-0378-z. View

Bolouri H, Farrar J, Triche Jr T, Ries R, Lim E, Alonzo T . The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med. 2017; 24(1):103-112. PMC: 5907936. DOI: 10.1038/nm.4439. View

Federico C, Bruno F, Ragusa D, Clements C, Brancato D, Henry M . Chromosomal Rearrangements and Altered Nuclear Organization: Recent Mechanistic Models in Cancer. Cancers (Basel). 2021; 13(22). PMC: 8616464. DOI: 10.3390/cancers13225860. View

Tosi S, Hughes J, Scherer S, Nakabayashi K, Harbott J, Haas O . Heterogeneity of the 7q36 breakpoints in the t(7;12) involving ETV6 in infant leukemia. Genes Chromosomes Cancer. 2003; 38(2):191-200. DOI: 10.1002/gcc.10258. View

Kulkarni R, Kale V . Physiological Cues Involved in the Regulation of Adhesion Mechanisms in Hematopoietic Stem Cell Fate Decision. Front Cell Dev Biol. 2020; 8:611. PMC: 7366553. DOI: 10.3389/fcell.2020.00611. View

Deguchi Y, Kehrl J . Selective expression of two homeobox genes in CD34-positive cells from human bone marrow. Blood. 1991; 78(2):323-8. View

Naiel A, Vetter M, Plekhanova O, Fleischman E, Sokova O, Tsaur G . A Novel Three-Colour Fluorescence in Situ Hybridization Approach for the Detection of t(7;12)(q36;p13) in Acute Myeloid Leukaemia Reveals New Cryptic Three Way Translocation t(7;12;16). Cancers (Basel). 2013; 5(1):281-95. PMC: 3730311. DOI: 10.3390/cancers5010281. View

10.

Hanekamp D, Cloos J, Schuurhuis G . Leukemic stem cells: identification and clinical application. Int J Hematol. 2017; 105(5):549-557. DOI: 10.1007/s12185-017-2221-5. View

11.

van den Brink S, Alemany A, van Batenburg V, Moris N, Blotenburg M, Vivie J . Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids. Nature. 2020; 582(7812):405-409. DOI: 10.1038/s41586-020-2024-3. View

12.

Ballabio E, Cantarella C, Federico C, Di Mare P, Hall G, Harbott J . Ectopic expression of the HLXB9 gene is associated with an altered nuclear position in t(7;12) leukaemias. Leukemia. 2009; 23(6):1179-82. DOI: 10.1038/leu.2009.15. View

13.

Harrison K, Thaler J, Pfaff S, Gu H, Kehrl J . Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet. 1999; 23(1):71-5. DOI: 10.1038/12674. View

14.

Willier S, Rothamel P, Hastreiter M, Wilhelm J, Stenger D, Blaeschke F . CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy. Blood. 2020; 137(8):1037-1049. DOI: 10.1182/blood.2020006921. View

15.

Sherwood R, Chen T, Melton D . Transcriptional dynamics of endodermal organ formation. Dev Dyn. 2008; 238(1):29-42. PMC: 3756511. DOI: 10.1002/dvdy.21810. View

16.

Taketani T, Taki T, Sako M, Ishii T, Yamaguchi S, Hayashi Y . MNX1-ETV6 fusion gene in an acute megakaryoblastic leukemia and expression of the MNX1 gene in leukemia and normal B cell lines. Cancer Genet Cytogenet. 2008; 186(2):115-9. DOI: 10.1016/j.cancergencyto.2008.06.009. View

17.

Tosi S, Giudici G, Mosna G, Harbott J, Specchia G, Grosveld G . Identification of new partner chromosomes involved in fusions with the ETV6 (TEL) gene in hematologic malignancies. Genes Chromosomes Cancer. 1998; 21(3):223-9. View

18.

Khoury J, Solary E, Abla O, Akkari Y, Alaggio R, Apperley J . The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022; 36(7):1703-1719. PMC: 9252913. DOI: 10.1038/s41375-022-01613-1. View

19.

Dong Y, Shi O, Zeng Q, Lu X, Wang W, Li Y . Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol. 2020; 9:14. PMC: 7304189. DOI: 10.1186/s40164-020-00170-6. View

20.

De Moerloose B . CAR-T treatment of pediatric AML: a long and winding road. Blood. 2021; 137(8):1004-1006. DOI: 10.1182/blood.2020009406. View