Lau Colleen M, Nish Simone A, Yogev Nir, Waisman Ari, Reiner Steven L, Reizis Boris
Department of Pathology, New York University Langone Medical Center, New York, NY 10016 Department of Medicine, New York University Langone Medical Center, New York, NY 10016 Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032.
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032.
J Exp Med. 2016 Mar 7;213(3):415-31. doi: 10.1084/jem.20150642. Epub 2016 Feb 22.
A common genetic alteration in acute myeloid leukemia is the internal tandem duplication (ITD) in FLT3, the receptor for cytokine FLT3 ligand (FLT3L). Constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. Pre-leukemic mice with the Flt3(ITD) knock-in allele manifested an expansion of classical DCs (cDCs) and plasmacytoid DCs. The expansion originated in DC progenitors, was cell intrinsic, and was further enhanced in Flt3(ITD/ITD) mice. The mutation caused the down-regulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Both canonical Batf3-dependent CD8(+) cDCs and noncanonical CD8(+) cDCs were expanded and showed specific alterations in their expression profiles. Flt3(ITD) mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T (T reg) cells. Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity without T reg cells. Thus, the FLT3-ITD mutation directly affects DC development, indirectly modulating T cell homeostasis and supporting T reg cell expansion. We hypothesize that this effect of FLT3-ITD might subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner.
急性髓系白血病中一种常见的基因改变是FMS样酪氨酸激酶3（FLT3）的内部串联重复（ITD），FLT3是细胞因子FLT3配体（FLT3L）的受体。组成型激活的FLT3-ITD促进转化祖细胞的扩增，但对造血也有多效性作用。我们分析了FLT3-ITD对树突状细胞（DC）的影响，DC表达FLT3，并且通过给予FLT3L可实现扩增。携带Flt3(ITD)敲入等位基因的白血病前期小鼠表现出经典DC（cDC）和浆细胞样DC的扩增。这种扩增起源于DC祖细胞，是细胞内在性的，并且在Flt3(ITD/ITD)小鼠中进一步增强。该突变导致DC表面Flt3下调，并降低其对FLT3L的反应性。典型的依赖Batf3的CD8(+) cDC和非典型的CD8(+) cDC均发生扩增，并在其表达谱上表现出特异性改变。Flt3(ITD)小鼠表现出支持T细胞增殖的能力增强，包括调节性T（Treg）细胞的细胞外扩增。因此，这些小鼠在移植物抗宿主反应期间限制了同种异体反应性T细胞反应，但在没有Treg细胞的情况下无法控制自身免疫。因此，FLT3-ITD突变直接影响DC发育，间接调节T细胞稳态并支持Treg细胞扩增。我们推测FLT3-ITD的这种作用可能以细胞外方式破坏免疫监视并促进白血病发生。
