Nature：急性髓性白血病的一個發病機制

由美國哥倫比亞大學等處的研究人員在一個小鼠模型中發現，激發成骨細胞中的及-catenin發生突變，足以引發「急性髓性白血病」(AML)的發病。相關文章發表於2014年1月15日的《Nature》雜誌上。

成骨細胞系會影響長期再植造血幹細胞的數量和歸巢，造血幹細胞動員，血統的決定和B細胞淋巴細胞增殖。最近的一項小鼠研究中，成骨細胞被發現與白血病前期有關聯。然而，並沒有證據表明，成骨細胞可誘導白血病單個基因突變。

腫瘤微環境對腫瘤發生有深遠影響，而基質細胞的基因改變會幫助癌症形成。

Stavroula Kousteni及同事在一個小鼠模型中發現，激發成骨細胞中的及-catenin發生突變，足以引發「急性髓性白血病」(AML)的發病。這些突變觸發會激活造血細胞中的Notch信號通道的配體從成骨細胞中釋放;Notch通道的抑制會改善病情。

關於在骨髓增生病患者和AML患者中患-catenin信號作用增強的發現表明，一個類似的機制可能會促使人患白血病。這些結果表明，成骨細胞可以誘導急性髓性白血病遺傳改變，找出導致這種轉變的分子信號，並提供一個急性髓細胞性白血病潛在的新的藥物治療方法。

原文摘要：

Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts

Aruna Kode, John S. Manavalan, Ioanna Mosialou, Govind Bhagat, Chozha V. Rathinam,Na Luo, Hossein Khiabanian, Albert Lee, Vundavalli V. Murty, Richard Friedman, Andrea Brum, David Park, Naomi Galili, Siddhartha Mukherjee, Julie Teruya-Feldstein, Azra Raza,Raul Rabadan, Ellin Berman & Stavroula Kousteni

Cells of the osteoblast lineage affect the homing and the number of long-term repopulating haematopoietic stem cells, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis. Osteoblasts were recently implicated in pre-leukaemic conditions in mice. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of β-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand jagged 1 in osteoblasts. Subsequent activation of Notch signalling in haematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacological inhibition of Notch signalling ameliorates acute myeloid leukaemia and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, increased β-catenin signalling and nuclear accumulation was identified in osteoblasts and these patients showed increased Notch signalling in haematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce acute myeloid leukaemia, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to acute myeloid leukaemia.