MLL-AF4 Acute Lymphocytic Leukemia (ALL) has a poor prognosis. We show that re-expression of miR-128b and miR-221, downregulated in MLL rearranged ALL, synergistically sensitizes MLL-AF4 ALL cells to glucocorticoids. Target genes downregulated by miR-128b include MLL, AF4, and both MLL-AF4 and AF4-MLL fusion genes; miR-221 downregulates CDKN1B. Finally we identified a novel A to G point mutation in the miR-128b gene in some MLL-AF4 ALL cells, which significantly reduces the processing of precursor miR-128b miRNA to the mature miRNA. These results demonstrate that downregulation of miR-128b and miR-221 induces glucocorticoid resistance, restoration of their levels is a promising therapeutic in MLL-AF4 ALL, and the A to G point mutation might pathophysiologically contribute to MLL-AF4 ALL.

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