Transcriptional variability facilitates stochastic cell diversification and can in turn underpin adaptation to stress or injury. We hypothesize that it may analogously facilitate progression of premalignancy to cancer. To investigate this, we initiated preleukemia in mouse cells with enhanced transcriptional variability due to conditional disruption of the histone lysine acetyltransferase gene Kat2a . By combining single-cell RNA sequencing of preleukemia with functional analysis of transformation, we show that Kat2a loss results in global variegation of cell identity and accumulation of preleukemic cells. Leukemia progression is subsequently facilitated by destabilization of ribosome biogenesis and protein synthesis, which confer a transient transformation advantage. The contribution of transcriptional variability to early cancer evolution reflects a generic role in promoting cell fate transitions, which, in the case of well-adapted malignancies, contrastingly differentiates and depletes cancer stem cells. That is, transcriptional variability confers forward momentum to cell fate systems, with differential multistage impact throughout cancer evolution.

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.

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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