The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME.
The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME.
Exp Hematol. 2020 Sep;89:61-67.e3. doi: 10.1016/j.exphem.2020.07.012. Epub 2020 Aug 6.
The MLL-AF9 fusion protein occurring as a result of t(9;11) translocation gives rise to pediatric and adult acute leukemias of distinct lineages, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and mixed-phenotype acute leukemia (MPAL). The mechanisms underlying how this same fusion protein results in diverse leukemia phenotypes among different individuals are not well understood. Given emerging evidence from genome-wide association studies that genetic risk factors contribute to MLL-rearranged leukemogenesis, here we tested the impact of genetic background on survival and phenotype of a well-characterized Mll-AF9 knockin mouse model. We crossed this model with five distinct inbred strains (129, A/J, C57BL/6, NOD, CAST) and tested their F1 hybrid progeny for dominant genetic effects on Mll-AF9 phenotypes. We discovered that genetic background altered peripheral blood composition, with Mll-AF9 CAST F1 having a significantly increased B-lymphocyte frequency, while the remainder of the strains exhibited myeloid-biased hematopoiesis, similar to the parental line. Genetic background also had an impact on overall survival, with Mll-AF9 A/J F1 and Mll-AF9 129 F1 having significantly shorter survival and Mll-AF9 CAST F1 having longer survival, compared with the parental line. Furthermore, we observed a range of hematologic malignancies, with Mll-AF9 A/J F1, Mll-AF9 129 F1, and Mll-AF9 B6 F1 developing exclusively myeloid cell malignancies (myeloproliferative disorder [MPD] and AML), whereas a subset of Mll-AF9 NOD F1 developed MPAL and Mll-AF9 CAST F1 developed ALL. This study provides a novel in vivo experimental model in which to evaluate the underlying mechanisms by which MLL-AF9 results in diverse leukemia phenotypes and provides definitive experimental evidence that genetic risk factors contribute to survival and phenotype of MLL-rearranged leukemogenesis.
MLL-AF9 融合蛋白是由于 t(9;11)易位产生的，导致儿科和成人急性白血病具有不同的谱系，包括急性淋巴细胞白血病（ALL）、急性髓系白血病（AML）和混合表型急性白血病（MPAL）。导致同一融合蛋白在不同个体中产生不同白血病表型的机制尚不清楚。鉴于全基因组关联研究的新证据表明遗传风险因素有助于 MLL 重排白血病的发生，我们在这里测试了遗传背景对经过充分特征描述的 Mll-AF9 敲入小鼠模型的生存和表型的影响。我们将该模型与五个不同的近交系（129、A/J、C57BL/6、NOD、CAST）杂交，并测试了它们的 F1 杂种后代对 Mll-AF9 表型的显性遗传效应。我们发现遗传背景改变了外周血成分，Mll-AF9 CAST F1 的 B 淋巴细胞频率显著增加，而其余的品系表现出骨髓偏向性造血，类似于亲本系。遗传背景对整体生存也有影响，与亲本系相比，Mll-AF9 A/J F1 和 Mll-AF9 129 F1 的生存时间明显缩短，而 Mll-AF9 CAST F1 的生存时间较长。此外，我们观察到一系列血液恶性肿瘤，Mll-AF9 A/J F1、Mll-AF9 129 F1 和 Mll-AF9 B6 F1 仅发展为髓系细胞恶性肿瘤（骨髓增生异常/白血病），而一部分 Mll-AF9 NOD F1 发展为混合表型急性白血病，而 Mll-AF9 CAST F1 发展为急性淋巴细胞白血病。这项研究提供了一个新的体内实验模型，可用于评估 MLL-AF9 导致不同白血病表型的潜在机制，并提供了明确的实验证据，证明遗传风险因素有助于 MLL 重排白血病的生存和表型。
