In normal hematopoiesis, GATA2 is highly expressed in the most immature HSCs and multipotent progenitors (MPP1 and MMP2) but less in other progenitors. Transformation by the MLLAF9 fusion oncogene generates highGata2-expressing cells (red) that are more resistant to chemotherapy than lowGata2-expressing cells (blue). Molecularly, highGata2 AML cells exhibited high ERG expression and high MECOM motif accessibility on chromatin, strongly repressed RASSF4 gene expression, TP53 inactivation through high MDM2 level, and chemoresistance. In contrast,lowGata2 leukemic cells showed higher RASSF4 expression, possibly through a positive regulation by SPI1. It is proposed that RASSF4 inhibits MDM2 favoring TP53 activation and a chemosensitive state. Inactivation of Gata2 in highGata2 as well as combined treatment with the TP53-MDM2 inhibitor nutlin-3a resensitized them to chemotherapy (Chemo).

In normal hematopoiesis, GATA2 is highly expressed in the most immature HSCs and multipotent progenitors (MPP1 and MMP2) but less in other progenitors. Transformation by the MLLAF9 fusion oncogene generates highGata2-expressing cells (red) that are more resistant to chemotherapy than lowGata2-expressing cells (blue). Molecularly, highGata2 AML cells exhibited high ERG expression and high MECOM motif accessibility on chromatin, strongly repressed RASSF4 gene expression, TP53 inactivation through high MDM2 level, and chemoresistance. In contrast,lowGata2 leukemic cells showed higher RASSF4 expression, possibly through a positive regulation by SPI1. It is proposed that RASSF4 inhibits MDM2 favoring TP53 activation and a chemosensitive state. Inactivation of Gata2 in highGata2 as well as combined treatment with the TP53-MDM2 inhibitor nutlin-3a resensitized them to chemotherapy (Chemo).

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