Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative neoplasm that bears distinct characteristics associated with abnormal fetal development. JMML has been extensively modeled in mice expressing the oncogenic Kras^G12D mutation. However, these models have struggled to recapitulate the defining features of JMML due to in utero lethality, nonhematopoietic expression, and the pervasive emergence of T cell acute lymphoblastic leukemia. Here, we have developed a model of JMML using mice that express Kras^G12D in multipotent progenitor cells (Flt3Cre⁺ Kras^G12D mice). These mice express Kras^G12D in utero, are born at normal Mendelian ratios, develop hepatosplenomegaly, anemia, and thrombocytopenia, and succumb to a rapidly progressing and fully penetrant neonatal myeloid disease. Mutant mice have altered hematopoietic stem and progenitor cell populations in the BM and spleen that are hypersensitive to granulocyte macrophage–CSF due to hyperactive RAS/ERK signaling. Biased differentiation in these progenitors results in an expansion of neutrophils and DCs and a concomitant decrease in T lymphocytes. Flt3Cre⁺ Kras^G12D fetal liver hematopoietic progenitors give rise to a myeloid disease upon transplantation. In summary, we describe a Kras^G12D mouse model that reproducibly develops JMML-like disease. This model will prove useful for preclinical drug studies and for elucidating the developmental origins of pediatric neoplasms.

中文翻译：

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在造血多能祖细胞中表达Kras ^G12D的小鼠发展为新生儿骨髓性白血病

少年骨髓单核细胞白血病（JMML）是一种小儿骨髓增生性肿瘤，具有与异常胎儿发育相关的独特特征。JMML已在表达致癌性Kras ^G12D突变的小鼠中进行了广泛建模。但是，由于子宫内致死率，非造血细胞表达和T细胞急性淋巴细胞白血病的普遍出现，这些模型难以概括JMML的定义特征。在这里，我们使用在多能祖细胞中表达Kras ^G12D的小鼠（Flt3Cre ⁺ Kras ^G12D小鼠）开发了JMML模型。这些小鼠表达了Kras ^G12D在子宫内，按正常的孟德尔比例出生，发展为肝脾肿大，贫血和血小板减少症，并死于快速发展且完全渗透的新生儿骨髓病。突变小鼠已经改变了BM和脾脏中造血干细胞和祖细胞的数量，由于过度活跃的RAS / ERK信号转导，它们对粒细胞巨噬细胞CSF过敏。这些祖细胞的偏向分化导致嗜中性粒细胞和DC的扩增，并伴随着T淋巴细胞的减少。Flt3Cre ⁺ Kras ^G12D胎儿肝造血祖细胞在移植后会引起髓样疾病。总而言之，我们描述了Kras ^G12D可重复发展为JMML样疾病的小鼠模型。该模型将被证明可用于临床前药物研究以及阐明小儿肿瘤的起源。