1016 – MHC II-DRIVEN IMMUNITY IN MALIGNANT HEMATOPOIETIC STEM AND PROGENITOR CELLS

IF 2.7 4区医学 Q2 HEMATOLOGY

Experimental hematology Pub Date : 2026-10-01 Epub Date: 2026-10-23 DOI:10.1016/j.exphem.2026.105512

Wei Tong, Ruoxing Wang, Mohammed Alhusayan, Eric Wafula, Bowen Xing, Emma Hedgepeth, Kaosheng Lv, Alexander Perl, Yan Liu, Hamid Band, Lawrence Eisenlohr, Junwei Shi, Irfan Asangani

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引用次数: 0

Abstract

Hematopoietic stem and progenitor cells (HSPCs) express major histocompatibility complex class II (MHC II or human leukocyte antigen, HLA-II) to enable immune surveillance. Reduced MHC II expression in acute myeloid leukemia (AML) is strongly associated with immune escape and relapse following allogeneic stem cell transplantation, yet the mechanisms regulating MHC II in HSPCs or AML are poorly established. Here, we identified Casitas B-lineage lymphoma (CBL) family E3 ubiquitin ligases—frequently mutated in various myeloid malignancies—as critical regulators of MHC II in both normal and malignant HSPCs. Genetic loss or mutation of CBL markedly reduces MHC II expression in stem-like AML cells and in HSPCs from Cbl/Cblb-deficient mice, impairing antigen presentation. Mechanistically, CBL inactivation downregulates the ETS-related gene (ERG), a heptad transcription factor essential for normal and leukemic stem cells. ERG binds to a previously unrecognized HSPC-specific class II MHC transactivator (CIITA) enhancer to sustain MHC II expression. Consistent with this mechanism, stem-like blasts from CBL-mutant primary AMLs and juvenile myelomonocytic leukemias (JMMLs) exhibit diminished MHC II expression. These findings uncover an HSPC-specific ERG-CIITA-MHC II regulatory axis linking oncogenic signaling to immune evasion, highlighting a potential therapeutic strategy to restore immune surveillance.

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恶性造血干细胞和祖细胞MHC ii驱动免疫

造血干细胞和祖细胞（HSPCs）表达主要组织相容性复合体II类（MHC II或人白细胞抗原，HLA-II），以实现免疫监视。急性髓性白血病（AML）中MHC II表达的降低与同种异体干细胞移植后的免疫逃逸和复发密切相关，但在HSPCs或AML中调节MHC II的机制尚不明确。在这里，我们发现Casitas b系淋巴瘤（CBL）家族E3泛素连接酶——在各种髓系恶性肿瘤中经常发生突变——在正常和恶性HSPCs中都是MHC II的关键调节因子。CBL基因缺失或突变可显著降低干细胞样AML细胞和CBL / cblb缺陷小鼠造血干细胞中MHC II的表达，损害抗原递呈。从机制上讲，CBL失活下调了ets相关基因（ERG），这是正常和白血病干细胞所必需的七肽转录因子。ERG结合先前未被识别的hspc特异性II类MHC转录激活子（CIITA）增强子来维持MHC II的表达。与这一机制一致，来自cbl突变的原发aml和幼年型髓细胞白血病（JMMLs）的干细胞样细胞表现出MHC II表达的减少。这些发现揭示了hspc特异性的ERG-CIITA-MHC II调节轴，将致癌信号与免疫逃避联系起来，强调了恢复免疫监视的潜在治疗策略。造血干细胞和祖细胞（HSPCs）表达主要组织相容性复合体II类（MHC II或人白细胞抗原，HLA-II），以实现免疫监视。急性髓性白血病（AML）中MHC II表达的降低与同种异体干细胞移植后的免疫逃逸和复发密切相关，但在HSPCs或AML中调节MHC II的机制尚不明确。在这里，我们发现Casitas b系淋巴瘤（CBL）家族E3泛素连接酶——在各种髓系恶性肿瘤中经常发生突变——在正常和恶性HSPCs中都是MHC II的关键调节因子。CBL基因缺失或突变可显著降低干细胞样AML细胞和CBL / cblb缺陷小鼠造血干细胞中MHC II的表达，损害抗原递呈。从机制上讲，CBL失活下调了ets相关基因（ERG），这是正常和白血病干细胞所必需的七肽转录因子。ERG结合先前未被识别的hspc特异性II类MHC转录激活子（CIITA）增强子来维持MHC II的表达。与这一机制一致，来自cbl突变的原发aml和幼年型髓细胞白血病（JMMLs）的干细胞样细胞表现出MHC II表达的减少。这些发现揭示了hspc特异性的ERG-CIITA-MHC II调节轴，将致癌信号与免疫逃避联系起来，强调了恢复免疫监视的潜在治疗策略。

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来源期刊

Experimental hematology 医学-血液学

CiteScore

5.30

自引率

0.00%

发文量

审稿时长

58 days

期刊介绍： Experimental Hematology publishes new findings, methodologies, reviews and perspectives in all areas of hematology and immune cell formation on a monthly basis that may include Special Issues on particular topics of current interest. The overall goal is to report new insights into how normal blood cells are produced, how their production is normally regulated, mechanisms that contribute to hematological diseases and new approaches to their treatment. Specific topics may include relevant developmental and aging processes, stem cell biology, analyses of intrinsic and extrinsic regulatory mechanisms, in vitro behavior of primary cells, clonal tracking, molecular and omics analyses, metabolism, epigenetics, bioengineering approaches, studies in model organisms, novel clinical observations, transplantation biology and new therapeutic avenues.