HOXA11 plays critical roles in disease progression and response to cytarabine in AML

Lysine methyltransferase 2A (KMT2A, also known as MLL) translocations (MLL-t) are frequently associated with mutations in RAS pathway genes in acute myeloid leukemia (AML). Previous findings with a mouse model showed that cooperation of MLL/AF10 with tyrosine-protein phosphatase non-receptor type 11 (PTPN11)(G503A) accelerated leukemia development, but increased cytarabine (Ara-C) sensitivity of leukemia cells. To identify the genes responsible for reduced survival and Ara-C resistance, transcriptomic profiling between six pairs of mouse MLL/AF10(OM-LZ) leukemia cells harboring activating and wild-type KRAS or PTPN11 was compared. A total of 23 differentially expressed genes (DEGs) with >1.5-fold-change between the paired cell lines were identified. The Gene Ontology (GO) terms overrepresented in these 23 DEGs included ‘immune system process’, ‘actin filament binding’, ‘cellular response to interferon-alpha’ and ‘sequence-specific DNA’. Among the four genes (Hoxa11, PR domain zinc finger protein 5, Iroquois-class homeodomain protein IRX-5 and homeobox protein PKNOX2) mapped to the GO term ‘sequence-specific DNA’, HOXA11 upregulation was associated with AML harboring MLL-t and RAS signaling mutations based on a meta-analysis using data deposited in Oncomine™ and analysis of the clinical samples in the present study. Microarray data revealed that only Hoxa11 was upregulated in those cells harboring activating PTPN11. Functional studies of Hoxa11 knockdown or overexpression in MLL/AF10(OM-LZ) cells revealed that Hoxa11 expression levels were associated with survival in vivo and Ara-C sensitivity/apoptosis in vitro. In addition, Hoxa11 regulated the expression of the apoptosis-related genes, NF-κB inhibitor α, transcription factor p65 and transformation-related protein p53. Furthermore, the results of a meta-analysis using Heuser's AML dataset supported the finding that chemotherapy responders have higher expression levels of HOXA11. These results indicated that the expression of HOXA11 increased cell apoptosis and predicted an improved response to Ara-C in AML.