Expression of MLL-ENL in hematopoietic stem cells induces mixed lineage acute leukemia

The t(11;19)(q23;p13.3) translocation leading to the expression of an MLL-ENL fusion is one of the most prevalent alterations affecting the mixed lineage leukemia 1 (MLL1) gene, mostly associated with B-cell acute lymphoblastic leukemia (ALL). Using a doxycycline (DOX)-inducible transgenic mouse model (“iMLL-ENL”) we show that direct induction or induction following transplantation of hematopoietic stem cells (HSC) but not of committed myeloid granulocyte-macrophage progenitors (GMP) leads to reversible acute mixed lineage leukemia. Disease induction was associated with iMLL-ENL levels exceeding the endogenous Mll1. iMLL-ENL leukemia was composed of small B220High cells with higher leukemia-initiating potential than co-existing larger-sized B220Low cells. Collectively, characterization of a novel transgenic mouse model indicates that the cell-of-origin and the expression levels above Mll1/MLL1 are both critical determinants for mixed lineage leukemia induced by the MLL-ENL fusion. Overall design: RNA-sequencing of hematopoietic stem cells in control and iMLL-ENLleukemic mice (total bone marrow or sorted for HIGH and LOW expression levels of the surface marker B220)

t(11;19)(q23;p13.3)易位可诱导MLL-ENL融合基因表达，该变异是累及混合谱系白血病1（mixed lineage leukemia 1, MLL1）基因的最常见基因改变之一，且多与B细胞急性淋巴细胞白血病（B-cell acute lymphoblastic leukemia, ALL）相关。本研究借助多西环素（doxycycline, DOX）诱导型转基因小鼠模型（命名为"iMLL-ENL"），证实直接诱导该融合基因表达，或对造血干细胞（hematopoietic stem cells, HSC）进行移植后再诱导，均可引发可逆性急性混合谱系白血病；而针对定型髓系粒细胞-巨噬细胞祖细胞（committed myeloid granulocyte-macrophage progenitors, GMP）开展相同操作则无法诱导疾病发生。疾病诱导与iMLL-ENL的表达水平高于内源性Mll1密切相关。iMLL-ENL相关白血病由小型B220High细胞构成，这类细胞的白血病起始潜能高于共存的大型B220Low细胞。综上，通过对该新型转基因小鼠模型的表征分析可知，细胞起源以及表达水平高于Mll1/MLL1这两个关键要素，均是MLL-ENL融合基因诱导混合谱系白血病的核心决定因素。整体实验设计：对对照组与iMLL-ENL白血病小鼠的造血干细胞进行RNA测序，样本采集方式包括提取全骨髓，或按表面标志物B220的高、低表达水平进行分选后提取。