High-risk acute lymphoblastic leukemia cells with bcr-abl and INK4A/ARF mutations retain susceptibility to alloreactive T cells.
High-risk acute lymphoblastic leukemia cells with bcr-abl and INK4A/ARF mutations retain susceptibility to alloreactive T cells.
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具有 bcr-abl 和 INK4A/ARF 突变的高危急性淋巴细胞白血病细胞保留对同种异体反应性 T 细胞的敏感性。
DOI：
10.1016/j.bbmt.2008.02.015
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Mullen,CraigA
中科院分区：
文献类型：
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作者：
Young,FaithM;Campbell,Andrew;Emo,KrisLambert;Jansson,Johan;Wang,Pin-Yi;Jordan,CraigT;Mullen,CraigA
INK 4A/ARF突变在bcr/abl+淋巴母细胞期慢性粒细胞白血病（CML）和bcr/abl+急性淋巴细胞白血病（ALL）中获得。供体淋巴细胞输注和移植物抗白血病（GVL）通常对此类ALL无效，而GVL对bcr/abl+CML高度活跃，而CML在INK 4A/ARF基因座上没有病变。GVL无效的机制尚不完全清楚，可能是急性淋巴细胞白血病对与同种异体GVL相关的免疫效应物的内在抗性可能导致无效。这项工作验证了以下假设：与bcr/abl+CML转化为ALL表型相关的INK 4A/ARF突变，以及与细胞凋亡抗性增加相关的INK 4A/ARF突变，使ALL细胞对次要组织相容性抗原（mHA）的同种异体免疫反应不敏感。通过将人p210 bcr/abl基因转移到INK 4A/ARF敲除小鼠的骨髓中来诱导小鼠急性前B ALL。然后在MHC匹配、mHA错配的同种异体BMT的鼠模型中研究这些ALL系。与同基因移植中的行为相比，这些ALL的体内生长在异基因移植中受到抑制，其特征是活跃的异基因免疫反应。在体外，具有INK 4A/ARF、p210 bcr/abl或p190 bcr/abl突变的ALL仍然对抗mHA细胞溶解性T细胞敏感。此外，ALL能够在体内诱导对mHA的初次免疫应答。因此，具有INK 4A/ARF或bcr/abl突变的ALL对同种异体T细胞应答并不具有内在抗性，这表明针对mHA的主动免疫疗法具有控制此类急性淋巴细胞白血病的潜力。
INK4A/ARF mutations are acquired in bcr/abl+lymphoid blast phase chronic myelogenous leukemia (CML) and bcr/abl+acute lymphoblastic leukemia (ALL). Donor lymphocyte infusion and graft-versus-leukemia (GVL) are generally ineffective in such ALLs, whereas GVL is highly active against bcr/abl+CML, which does not have a lesion in the INK4A/ARF locus. The mechanisms for the ineffectiveness of GVL are not fully known, and it is possible that intrinsic resistance of acute lymphoid leukemias to immune effectors associated with allogeneic GVL may contribute to ineffectiveness. This work tested the hypothesis that INK4A/ARF mutations that are associated with transformation of bcr/abl+CML to an ALL phenotype, and that are associated with increased resistance to apoptosis render ALL cells insensitive to allogeneic immune responses to minor histocompatibility antigens (mHA). Murine acute pre-B ALLs were induced by transfer of the human p210 bcr/abl gene into bone marrow of INK4A/ARF null mice. These ALL lines were then studied in a murine model of MHC-matched, mHA-mismatched allogeneic BMT. In vivo growth of these ALLs was inhibited in allogeneic transplants characterized by active allogeneic immune responses compared to their behavior in syngeneic transplants. In vitro ALLs with INK4A/ARF, p210 bcr/abl, or p190 bcr/abl mutations remained sensitive to anti-mHA cytolytic T cells. In addition, the ALLs were capable of inducing primary immune responses to mHAs in vivo. Thus, ALLs with INK4A/ARF or bcr/abl mutations are not intrinsically resistant to allogeneic T cell responses, suggesting that active immunotherapies against mHA have the potential to control such acute lymphoblastic leukemias.