Next-Generation Sequencing Revealed a Distinct Immunoglobulin Repertoire with Specific Mutation Hotspots in Acute Myeloid Leukemia

Abstract

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.

Suggestion the role of antibodies/immunoglobulins, produced by non-lymphoid cells, tissues and organs, as participants in different regulatory mechanisms

“…The results obtained also suggested a possibility for non-lymphoid cellular types, including neoplastic cells, to express genes for immunoglobulins, which is in agreement with the literature data [11][12][13]. It is possible this feature to be a step of the cascade regulatory pathways, in which molecules like GSH participate, and it has been additionally con rmed by the high levels of expression of immunoglobulins by non-lymphoid myeloblasts and other types of malignant cells [19][20][21]. This phenomenon could be explained with a presence of sub-populations of stem-like cells, which are able to differentiate to various directions in dependence of the respective conditions, by taking in consideration that the genes in each cell in the composition of the respective tissue or organ are the same (independently of the cellular type of phase of differentiation and maturation).…”

“…High immunoglobulin expression by myeloblasts of patients with acute myeloid leukemia (AML) have been associated with monocytic differentiation, multilineage dysplasia, as well as mutations in cellular oncogenes (as gene K-RAS), and thus have been related with bad prognosis generally [19]. Therefore, antibodies produced by malignancies and malignant cells are proposed as new molecular markers on the one hand [20] and as a new therapeutic target on the other [21], for development of novel therapeutic strategies.…”