Infant and adult MLL1/KMT2A-rearranged (MLLr) leukemia represents a disease with a dismal prognosis. Here, we present a functional and proteomic characterization of in utero-initiated and adult-onset MLLr leukemia. We reveal that fetal MLL::ENL-expressing lymphomyeloid multipotent progenitors (LMPPs) are intrinsically programmed towards a lymphoid fate but give rise to myeloid leukemia in vivo, highlighting a complex interplay of intra- and extracellular factors in determining disease subtype. We characterize early proteomic events of MLL::ENL-mediated transformation in fetal and adult blood progenitors and reveal that whereas adult pre-leukemic cells are mainly characterized by retained myeloid features and downregulation of ribosomal and metabolic proteins, expression of MLL::ENL in fetal LMPPs leads to enrichment of translation-associated and histone deacetylases signaling proteins, and decreased expression of inflammation and myeloid differentiation proteins. Integrating the proteome of pre-leukemic cells with their secretome and the proteomic composition of the extracellular environment of normal progenitors highlights differential regulation of Igf2 bioavailability, as well as of VLA-4 dimer and its ligandome, upon initiation of fetal- and adult-origin leukemia, with implications for human MLLr leukemia cells’ ability to communicate with their environment through granule proteins. Our study has uncovered opportunities for targeting ontogeny-specific proteomic vulnerabilities in in utero-initiated and adult-onset MLLr leukemia.

婴儿和成人MLL1/KMT2A重排 (MLLr) 白血病是一种预后不佳的疾病。在这里，我们提出了子宫内起始和成人发病的 MLLr 白血病的功能和蛋白质组学特征。我们发现，表达MLL::ENL的胎儿淋巴骨髓多能祖细胞 (LMPP) 本质上被编程为淋巴命运，但在体内会引起骨髓性白血病，这凸显了细胞内和细胞外因素在确定疾病亚型时的复杂相互作用。我们描述了胎儿和成人血液祖细胞中MLL::ENL介导的转化的早期蛋白质组事件，并揭示了成人前白血病细胞的主要特征是保留骨髓特征以及核糖体和代谢蛋白的下调，而MLL::ENL的表达胎儿 LMPP 导致翻译相关蛋白和组蛋白脱乙酰酶信号蛋白富集，并减少炎症和骨髓分化蛋白的表达。将白血病前细胞的蛋白质组与其分泌组以及正常祖细胞的细胞外环境的蛋白质组组成进行整合，突显了胎儿和成人来源起始时 Igf2 生物利用度以及 VLA-4 二聚体及其配体组的差异调节白血病，对人类 MLLr 白血病细胞通过颗粒蛋白与其环境沟通的能力有影响。我们的研究发现了针对子宫内起始和成人发病的 MLLr 白血病个体发育特异性蛋白质组学漏洞的机会。