Abstract
Simple SummaryIdentifying new molecular targets is of great importance for prognosis prediction and target therapy of acute myeloid leukemia (AML). We previously reported on frequent expression of immunoglobulin (Ig) in myeloblasts. In this study, we investigated the clinical significance of Ig expression in sorted myeloblasts from 59 AML patients. We found that a higher level of AML-derived Ig expression correlated with a significantly shorter disease-free survival. Furthermore, we performed a comprehensive analysis of AML-derived Ig repertoire by next-generation sequencing (NGS) in 16 patients. The transcripts of AML-derived Ig shared some features with B cell-derived Ig, such as a typical V(D)J recombination and high mutation rates. However, they also showed distinct features. In contrast to the huge diversity of classical Ig, the VH-D-JH rearrangements used by AML-derived Ig were biased in each AML patient. In particularly, the Vκ-Jκ rearrangements were skewed in both AML blasts and normal peripheral blood mononucleated cells (PBMCs). However, AML-derived IGK showed high somatic mutation rates (>2%), while IGK in normal PBMCs rarely displayed hypermutation (<2%). More importantly, we identified five mutation hotspots at serine codons of IGKV3-20 in AML blasts, which may be involved in leukemogenesis and serve as a novel marker for disease monitoring and target therapy.Immunoglobulin (Ig) is known as a hallmark of B-lymphocytes exerting antibody functions. However, our previous studies demonstrated that myeloblasts from acute myeloid leukemia (AML) patients could also express Ig with distinct roles. Here, we quantified Ig (IGHG and IGK) transcripts by real-time PCR and performed a comprehensive analysis of Ig repertoire (both heavy chains and light chains) in AML blasts. We found that Ig was frequently expressed by AML blasts. A higher level of AML-derived IGHG expression correlated with a significantly shorter disease-free survival. Next-generation sequencing revealed dysregulated transcripts of all five Ig classes (IGHA, IGHD, IGHE, IGHG, and IGHM) and two Ig types (IGK and IGL) in AML. VH-D-JH rearrangements in myeloblasts were biased with individual specificity rather than generally diverse as in B-cells. Compared to AML-derived IgH, AML-derived IGK was more conserved among different AML samples. The frequently shared Vκ-Jκ patterns were IGKV3-20*01/IGKJ1*01, IGKV2D-28*01/IGKJ1*01, and IGKV4-1*01/IGKJ1*01. Moreover, AML-derived IGK was different from classical IGK in B-cells for the high mutation rates and special mutation hotspots at serine codons. Findings of the distinct Ig repertoire in myeloblasts may facilitate the discovery of a new molecular marker for disease monitoring and target therapy.
Highlights
Acute myeloid leukemia (AML) is a group of genetically heterogeneous diseases characterized by abnormal overproduction of immature myeloid cells, resulting in hematopoiesis impairment and bone marrow failure [1,2]
We further evaluated the expression of Ig transcripts in myeloblasts from 59 AML patients
We could not find a common dominant pattern among different AML samples. This is different from our previous studies of epithelial cancer cell-derived IgH, in which we identified highly conserved IgH sequences [40], showing IGHV3-15/IGHD3-10/IGHJ4, IGHV6-1/IGHD6-3/IGHJ4, and IGHV4-30/IGHD3-22/IGHJ4 mainly used by IGHM, and IGHV5-51/IGHD3-9/IGHJ4 frequently used by IGHG
Summary
Acute myeloid leukemia (AML) is a group of genetically heterogeneous diseases characterized by abnormal overproduction of immature myeloid cells, resulting in hematopoiesis impairment and bone marrow failure [1,2]. Despite the advances in combined chemotherapy and hematopoietic stem cell transplantation, the survival rate of AML patients has not been remarkably improved in the past years. It has been reported that molecular genetic aberrations can be detected in approximately 90% of AML patients [3,4]. AML patients can be stratified into favorable, intermediate, or adverse prognostic risk groups based on their cytogenetic and mutation profile. About sixty mutations in genes, such as FLT3, NPM1, CEBPA, IDH1, IDH2, KIT, RUNX1, and TP53, have helped further refine risk stratification and precise therapy [5,6]. Identifying new molecular targets is of great importance for guiding risk stratification, and monitoring minimal/measurable residual disease (MRD) and developing targeted therapy
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