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Summary: Upregulation of the Wilms' tumour 1 (WT1) gene is common in acute myeloid leukaemia (AML) and is associated with poor prognosis. WT1 generates 12 primary transcripts through different translation initiation sites and alternative splicing. The short WT1 transcripts express abundantly in primary leukaemia samples. We observed that overexpression of short WT1 transcripts lacking exon 5 with and without the KTS motif (sWT1+/− and sWT1−/−) led to reduced cell growth. However, only sWT1+/− overexpression resulted in decreased CD71 expression, G1 arrest, and cytarabine resistance. Primary AML patient cells with low CD71 expression exhibit resistance to cytarabine, suggesting that CD71 may serve as a potential biomarker for chemotherapy. RNAseq differential expressed gene analysis identified two transcription factors, HOXA3 and GATA2, that are specifically upregulated in sWT1+/− cells, whereas CDKN1A is upregulated in sWT1−/− cells. Overexpression of either HOXA3 or GATA2 reproduced the effects of sWT1+/−, including decreased cell growth, G1 arrest, reduced CD71 expression and cytarabine resistance. HOXA3 expression correlates with chemotherapy response and overall survival in NPM1 mutation‐negative leukaemia specimens. Overexpression of HOXA3 leads to drug resistance against a broad spectrum of chemotherapeutic agents. Our results suggest that WT1 regulates cell proliferation and drug sensitivity in an isoform‐specific manner. [ABSTRACT FROM AUTHOR]

Interestingly, THZ531 area under the curve (AUC) values exhibited a strong negative correlation with Venetoclax (Figure 1C), suggesting that CDK12/CDK13 inhibitors may be effective in the cases refractory/resistant to Venetoclax-based treatments. Strikingly, THZ531 and SR-4835 were sensitive in all three samples tested (Figure 1F), further validating that CDK12/CDK13 inhibitors can overcome Venetoclax resistance. The presented data highlights the contrasting sensitivities of THZ531 and Venetoclax in leukaemia samples and proposes the potential of THZ531 to overcome drug resistance associated with Venetoclax-based therapy. [Extracted from the article]