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

Weichenhan, Dieter; Riedel, Anna; Sollier, Etienne; Toprak, Umut H.; Hey, Joschka; Breuer, Kersten; Wierzbinska, Justyna A.; Touzart, Aurore; Lutsik, Pavlo; Bähr, Marion; Östlund, Anders; Nilsson, Tina; Jacobsson, Susanna; Edler, Marcel; Waraky, Ahmed; Behrens, Yvonne Lisa; Göhring, Gudrun; Schlegelberger, Brigitte; Steinek, Clemens; Harz, Hartmann; Leonhardt, Heinrich; Dolnik, Anna; Reinhard, Dirk; Bullinger, Lars; Palmqvist, Lars; Lipka, Daniel B.; Plass, Christoph

doi:10.1101/2023.09.13.557546

Cited by 2 publications

(1 citation statement)

References 61 publications

(164 reference statements)

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“…Indeed, the translocated intron 1 of ETV6 contains numerous enhancers and regulatory elements that may drive MNX1 overexpression, mimicking the molecular mechanism described for canonical t(7;12) cases [11]. Of note, a recent study points to an enhancer-hijacking event activating the MNX1 promoter from the ETV6 locus as an explanation for the MNX1 overexpression in this AML subtype [15]. Overall, these observations support that MNX1, rather than NOM1, is most likely the driver event of the disease, akin to other t(7;12) leukemias [13].…”

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confidence: 77%

Backtracking NOM1::ETV6 fusion to neonatal pathogenesis of t(7;12) (q36;p13) infant AML

Bousquets-Muñoz,

Molina,

Varela

et al. 2024

Leukemia

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Acute leukemia is the most frequently diagnosed malignancy in childhood, with acute lymphoblastic leukemia (ALL) comprising approximately 80% of cases in children aged 0-18 years, and acute myeloid leukemia (AML) accounting for approximately 15-20% [1]. The early onset (0-10 years) of most childhood acute leukemias and the high concordance rate among monozygotic twins suggest a prenatal origin of the disease [1]. Indeed, the presence of preleukemic precursors in cord blood (CB) samples or Guthrie blood spots from children who later developed acute leukemia has been demonstrated in several studies [2,3]. However, this has mainly been demonstrated experimentally for the most common cytogenetic subtypes, particularly in ALL.The most prevalent genetic abnormality in infants (up to 1 year of age) with AML (iAML) is chromosome 11q23 translocations involving the KMT2A gene. This occurs at a higher incidence in children than in adults (38% vs 2%), with the highest incidence in infants (77%), suggesting that infant and adult AMLs are distinct biological entities. Notably, iAML may have an in utero origin [4], as demonstrated by long-established evidence of a prenatal origin for MLL rearrangements [5]. In fact, the t(8;21)(q22;q22) AML subgroup has also been associated with a prenatal origin [3]. However, studies of patients with AML in different molecular subgroups have failed to detect the corresponding genetic alteration in the respective CB or Guthrie blood spot samples [6], suggesting a less frequent prenatal origin of AML compared to ALL.The t(7;12)(q36;p13) is a recurrent chromosomal rearrangement uniquely linked to AML. It ranks as the second most common abnormality in infants with AML, constituting nearly one-third of cases and associated with a dismal prognosis [7], with extremely poor survival rates and ineffective treatment by hematopoietic stem cell transplantation. Event-free survival rates (EFS) are 0-14%

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mentioning

confidence: 77%

Backtracking NOM1::ETV6 fusion to neonatal pathogenesis of t(7;12) (q36;p13) infant AML

Bousquets-Muñoz,

Molina,

Varela

et al. 2024

Leukemia

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Dissecting infant leukemia developmental origins with a hemogenic gastruloid model

Ragusa

Suen

Cortes

et al. 2022

Preprint

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Current in vitro models of developmental blood formation lack spatiotemporal coherence and weakly replicate the hematopoietic microenvironment. Developmentally-appropriate models can enhance understanding of infant acute myeloid leukemia (infAML), which putatively originates in utero and has 50% age-unique genetic events, suggesting unique biology. The commonest genetic abnormality unique to infants involves homeobox gene MNX1, whose leukemogenic mechanisms remain unknown. Recently, 3D self-organising embryonic stem cell (SC)-based gastruloids have shown promise in recapitulating embryonic events with time/space precision. Herein, we report a hemogenic gastruloid (haemGx) system that captures multi-wave blood formation, progenitor specification from hemogenic endothelium (HE), and approximates generation of hematopoietic SC precursors. Enforced MNX1 expression in haemGx promotes HE formation, perturbs endothelial-to-hemogenic transition, and critically achieves transformation, generating myeloid colonies which display MNX1 AML signatures. By combining functional assays with single-cell transcriptomics, we establish the haemGx as a new model of normal and leukemic embryonic hematopoiesis amenable to mechanistic exploration.

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Altered enhancer-promoter interaction leads toMNX1expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

Cited by 2 publications

References 61 publications

Backtracking NOM1::ETV6 fusion to neonatal pathogenesis of t(7;12) (q36;p13) infant AML

Backtracking NOM1::ETV6 fusion to neonatal pathogenesis of t(7;12) (q36;p13) infant AML

Dissecting infant leukemia developmental origins with a hemogenic gastruloid model

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