Wang Zhengqi, Medrzycki Magdalena, Bunting Silvia T, Bunting Kevin D
Department of Pediatrics, Division of Hematology-Oncology-BMT, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University, Atlanta GA, USA.
Department of Pathology, Children's Healthcare of Atlanta, Atlanta GA, USA.
Oncotarget. 2015 Oct 6;6(30):28961-72. doi: 10.18632/oncotarget.5009.
Despite being an attractive molecular target for both lymphoid and myeloid leukemias characterized by activated tyrosine kinases, the molecular and physiological consequences of reduced signal transducer and activator of transcription-5 (Stat5) during leukemogenesis are not well known. Stat5 is a critical regulator of mouse hematopoietic stem cell (HSC) self-renewal and is essential for normal lymphocyte development. We report that pan-hematopoietic deletion in viable adult Vav1-Cre conditional knockout mice as well as Stat5ab(null/null) fetal liver transplant chimeras generated HSCs with reduced expression of quiescence regulating genes (Tie2, Mpl, Slamf1, Spi1, Cited2) and increased expression of B-cell development genes (Satb1, Dntt, Btla, Flk2). Using a classical murine B-cell acute lymphoblastic leukemia (B-ALL) model, we demonstrate that these HSCs were also poised to produce a burst of B-cell precursors upon expression of Bcl-2 combined with oncogenic Myc. This strong selective advantage for leukemic transformation in the background of Stat5 deficient hematopoiesis was permissive for faster initiation of Myc-induced transformation to B-ALL. However, once established, the B-ALL progression in secondary transplant recipients was Stat5-independent. Overall, these studies suggest that Stat5 can play multiple important roles that not only preserve the HSC compartment but can limit accumulation of potential pre-leukemic lymphoid populations.
尽管信号转导及转录激活因子5（Stat5）是具有激活酪氨酸激酶特征的淋巴样和髓样白血病的一个有吸引力的分子靶点，但在白血病发生过程中Stat5减少的分子和生理后果尚不清楚。Stat5是小鼠造血干细胞（HSC）自我更新的关键调节因子，对正常淋巴细胞发育至关重要。我们报告，在成年存活的Vav1-Cre条件性敲除小鼠以及Stat5ab基因敲除（null/null）胎肝移植嵌合体中进行全造血细胞缺失，所产生的造血干细胞中静止调节基因（Tie2、Mpl、Slamf1、Spi1、Cited2）的表达降低，而B细胞发育基因（Satb1、Dntt、Btla、Flk2）的表达增加。使用经典的小鼠B细胞急性淋巴细胞白血病（B-ALL）模型，我们证明，在表达Bcl-2并结合致癌性Myc时，这些造血干细胞也易于产生大量B细胞前体。在Stat5缺陷造血背景下，白血病转化的这种强大选择优势有利于Myc诱导的向B-ALL转化更快启动。然而，一旦建立，二次移植受体中的B-ALL进展则不依赖于Stat5。总体而言，这些研究表明，Stat5可发挥多种重要作用，不仅能维持造血干细胞池，还能限制潜在白血病前淋巴细胞群体的积累。
