Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan.
Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Elife. 2021 Jul 26;10:e64148. doi: 10.7554/eLife.64148.
HOXA9 is often highly expressed in leukemias. However, its precise roles in leukemogenesis remain elusive. Here, we show that HOXA9 maintains gene expression for multiple anti-apoptotic pathways to promote leukemogenesis. In MLL fusion-mediated leukemia, MLL fusion directly activates the expression of MYC and HOXA9. Combined expression of MYC and HOXA9 induced leukemia, whereas single gene transduction of either did not, indicating a synergy between MYC and HOXA9. HOXA9 sustained expression of the genes implicated in the hematopoietic precursor identity when expressed in hematopoietic precursors, but did not reactivate it once silenced. Among the HOXA9 target genes, and synergistically induced leukemia with . Not only BCL2, but also SOX4 suppressed apoptosis, indicating that multiple anti-apoptotic pathways underlie cooperative leukemogenesis by HOXA9 and MYC. These results demonstrate that HOXA9 is a crucial transcriptional maintenance factor that promotes MYC-mediated leukemogenesis, potentially explaining why HOXA9 is highly expressed in many leukemias.
HOXA9 在白血病中常常高度表达。然而，其在白血病发生中的确切作用仍不清楚。在这里，我们表明 HOXA9 通过维持多个抗凋亡途径的基因表达来促进白血病发生。在 MLL 融合介导的白血病中，MLL 融合直接激活 MYC 和 HOXA9 的表达。MYC 和 HOXA9 的联合表达诱导白血病，而单独转导任一基因则不会，表明 MYC 和 HOXA9 之间存在协同作用。HOXA9 在造血前体细胞中表达时维持造血前体细胞特征相关基因的表达，但一旦沉默则不会重新激活它。在 HOXA9 的靶基因中， 和 与 协同诱导白血病。不仅 BCL2，而且 SOX4 也抑制凋亡，表明 HOXA9 和 MYC 协同诱导白血病的多个抗凋亡途径。这些结果表明，HOXA9 是一种关键的转录维持因子，可促进 MYC 介导的白血病发生，这可能解释了为什么 HOXA9 在许多白血病中高度表达。
