Figure 6.
MCT4 expression is induced by AML genes via histone epigenetic modification. (A) Quantitative PCR analysis of MCT4 mRNA expression at day 3 after MLL-AF9 OE in normal LKS in vitro (n = 6). (B) In vitro pHi of normal LKS with MLL-AF9 or MLL-AF9/MCT4 KD at day 3 postinfection (n = 4). (C) In vitro cellular growth of MLL-AF9–induced LKS with scrambled or MCT4 shRNA at day 6 postinfection (n = 3). (D) FACS analysis of MCT4 protein expression in human CB CD34+ cells retrovirally induced with MLL-AF9, HoxA9-Meis1, or KRASG12D (n = 4). (E) In vitro pHi of normal CB transduced with MLL-AF9 or KRASG12D carrying scrambled or MCT4 KD at day 3 postinfection (n = 4). (F) In vitro cellular growth of MLL-AF– or KRASG12D-induced LKS with scrambled/MCT4 shRNA at day 6 postinfection (n = 4). (G) ChIP PCR analysis of enrichment of histone activation mark H3K27ac on MCT4 promoter in mouse AML (MLL-AF9, HoxA9-Meis1, PML-RARα, and FLT3ITD/TET2−/−) and normal Lin− BM cells (n = 3). (H) ChIP PCR analysis of enrichment of H3K27ac on MCT4 promoter in human leukemic cell lines (n = 3). (I) ChIP PCR analysis of enrichment of H3K27ac on MCT4 promoter in primary human AML blasts (n = 5) and CB CD34+ cells (n = 3). (J) Correlation between H3K27ac enrichment on MCT4 promoter with MCT4 expression in primary AML samples (red square; n = 5) and CB CD34+ cells (black dot; n = 3). (K) ChIP PCR analysis of enrichment of H3K27ac on MCT4 promoter in MLL-AF9– or KRASG12D-transformed CB CD34+ cells (n = 3). (L-M) BRD4 (L) and H3K27ac (M) on MCT4 promoter in MLL-AF9 AML upon JQ-1 treatment in vitro (n = 3). (N) JQ-1 treatment on MCT4 expression of primary human AML (5 individual AML patient samples). (O) JQ-1 treatment on enrichment of H3K27ac on MCT4 promoter of primary human AML (4 individual AML patient samples). (P) JQ-1 treatment on growth of primary human AML (5 individual AML patient samples). (Q) In vivo BrdU incorporation assay in THP-1 upon MCT4 OE and JQ-1 treatment (n = 4). (R) Kaplan-Meier survival analysis of mice transplanted with THP-1 upon MCT4 OE and JQ-1 treatment (n = 10). Red area indicates JQ-1 treatment. (S) NF-κB inhibitor treatment on MCT4 expression of AML cell lines and KRASG12D-transformed CB (n = 3). (T) NF-κB inhibitor treatment on H3K27ac enrichment on MCT4 promoter of AML cell lines (n = 3). (U) HAT inhibitor treatment on MCT4 expression of AML cell lines and KRASG12D-transformed CB (n = 3). (V) HAT inhibitor treatment on MCT4 expression of primary human AML (8 individual AML patient samples). *P < .05, **P < .01, ***P < .001. ns, not significant.

MCT4 expression is induced by AML genes via histone epigenetic modification. (A) Quantitative PCR analysis of MCT4 mRNA expression at day 3 after MLL-AF9 OE in normal LKS in vitro (n = 6). (B) In vitro pHi of normal LKS with MLL-AF9 or MLL-AF9/MCT4 KD at day 3 postinfection (n = 4). (C) In vitro cellular growth of MLL-AF9–induced LKS with scrambled or MCT4 shRNA at day 6 postinfection (n = 3). (D) FACS analysis of MCT4 protein expression in human CB CD34+ cells retrovirally induced with MLL-AF9, HoxA9-Meis1, or KRASG12D (n = 4). (E) In vitro pHi of normal CB transduced with MLL-AF9 or KRASG12D carrying scrambled or MCT4 KD at day 3 postinfection (n = 4). (F) In vitro cellular growth of MLL-AF– or KRASG12D-induced LKS with scrambled/MCT4 shRNA at day 6 postinfection (n = 4). (G) ChIP PCR analysis of enrichment of histone activation mark H3K27ac on MCT4 promoter in mouse AML (MLL-AF9, HoxA9-Meis1, PML-RARα, and FLT3ITD/TET2−/−) and normal Lin− BM cells (n = 3). (H) ChIP PCR analysis of enrichment of H3K27ac on MCT4 promoter in human leukemic cell lines (n = 3). (I) ChIP PCR analysis of enrichment of H3K27ac on MCT4 promoter in primary human AML blasts (n = 5) and CB CD34+ cells (n = 3). (J) Correlation between H3K27ac enrichment on MCT4 promoter with MCT4 expression in primary AML samples (red square; n = 5) and CB CD34+ cells (black dot; n = 3). (K) ChIP PCR analysis of enrichment of H3K27ac on MCT4 promoter in MLL-AF9– or KRASG12D-transformed CB CD34+ cells (n = 3). (L-M) BRD4 (L) and H3K27ac (M) on MCT4 promoter in MLL-AF9 AML upon JQ-1 treatment in vitro (n = 3). (N) JQ-1 treatment on MCT4 expression of primary human AML (5 individual AML patient samples). (O) JQ-1 treatment on enrichment of H3K27ac on MCT4 promoter of primary human AML (4 individual AML patient samples). (P) JQ-1 treatment on growth of primary human AML (5 individual AML patient samples). (Q) In vivo BrdU incorporation assay in THP-1 upon MCT4 OE and JQ-1 treatment (n = 4). (R) Kaplan-Meier survival analysis of mice transplanted with THP-1 upon MCT4 OE and JQ-1 treatment (n = 10). Red area indicates JQ-1 treatment. (S) NF-κB inhibitor treatment on MCT4 expression of AML cell lines and KRASG12D-transformed CB (n = 3). (T) NF-κB inhibitor treatment on H3K27ac enrichment on MCT4 promoter of AML cell lines (n = 3). (U) HAT inhibitor treatment on MCT4 expression of AML cell lines and KRASG12D-transformed CB (n = 3). (V) HAT inhibitor treatment on MCT4 expression of primary human AML (8 individual AML patient samples). *P < .05, **P < .01, ***P < .001. ns, not significant.

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