Rearrangement and expression of the immunoglobulin μ-chain gene in human myeloid cells

Abstract

Immunoglobulin (Ig), a characteristic marker of B cells, has been reported to be expressed in epithelial cells, with a suggested role in their growth and survival. We have previously reported that IgG heavy chain is expressed in acute myeloid leukemia (AML), but not in the monocytes or neutrophils from patients with non-hematopoietic neoplasms or healthy controls. In the present study, we assessed IgM heavy chain expression and repertoire in human myeloid cells. We detected V Hm DJ Hm rearrangement and expression in 7/7 AML cell lines, 7/14 primary myeloblasts from AML patients, and interestingly, 8/20 monocytes and 3/20 neutrophils from patients with non-hematopoietic neoplasms and healthy individuals. We also found evidence of somatic hypermutation of the variable (V) gene segments in AML-derived IgM gene rearrangements but not in IgM from monocytes or neutrophils from patients with non-hematopoietic neoplasms and healthy individuals. Furthermore, IgM V Hm DJ Hm gene rearrangements in AML cell lines, primary myeloblasts, and monocytes and neutrophils from patients with non-hematopoietic neoplasms showed a restricted V usage and repertoire, whereas the V Hm DJ Hm gene rearrangements in monocytes and neutrophils from healthy individuals displayed more diversity. Anti-human IgM inhibited cell proliferation, but did not induce apoptosis in AML cell lines. Our findings suggest that AML-derived IgM might be a novel AML-related molecule that is involved in leukemogenesis and AML progression and might serve as a useful molecular marker for designing targeted therapy and monitoring minimal residual disease.

High levels of immunoglobulin expression predict shorter overall survival in patients with acute myeloid leukemia

“…We also have shown that IgG can be expressed in myeloblasts, and it has unique VDJ rearrangements and has undergone somatic hypermutation 8‐10 . Furthermore, AML‐derived immunoglobulin has functional significance and is involved in proliferation, apoptosis, and migration of leukemic cells 8‐10 . These findings suggest that AML‐derived immunoglobulin may have a role in AML pathogenesis and progression, and could serve as a novel marker for monitoring residual disease and developing target therapy.…”

“…Although it was once presumed that B lymphocytes and plasma cells are the only sources of immunoglobulin, in the past decades it has been reported that immunoglobulin is expressed in many types of neoplastic epithelial cells 2‐5 and non‐neoplastic cells 6,7 . We also have shown that IgG can be expressed in myeloblasts, and it has unique VDJ rearrangements and has undergone somatic hypermutation 8‐10 . Furthermore, AML‐derived immunoglobulin has functional significance and is involved in proliferation, apoptosis, and migration of leukemic cells 8‐10 .…”

Clinical observations on chemotherapy curable malignancies: unique genetic events, frozen development and enduring apoptotic potential

“…In studies of AML, genetic analysis indicates that the immunoglobulin heavy chains genes have undergone VDJ rearrangement in 40–50% of cases and that the expression of the VDJ recombinase associated proteins RAG1 and RAG2 was also detectable in approximately 50% of cases [ 136 , 228 ]. More recent data confirms that VDJ recombination had occurred in the AML myeloblasts of 50% of patients and that there was also limited evidence of somatic hypermutation occurring [ 229 ]. In keeping with the observation that VDJ rearrangement is a common event in haematopoietic stem cells destined to proceed towards myeloid differentiation, evidence of significant level of earlier VDJ recombination but not somatic hypermutation are found in monocytes and neutrophils from healthy donors [ 229 ].…”

“…More recent data confirms that VDJ recombination had occurred in the AML myeloblasts of 50% of patients and that there was also limited evidence of somatic hypermutation occurring [ 229 ]. In keeping with the observation that VDJ rearrangement is a common event in haematopoietic stem cells destined to proceed towards myeloid differentiation, evidence of significant level of earlier VDJ recombination but not somatic hypermutation are found in monocytes and neutrophils from healthy donors [ 229 ]. It is possible that this presence of VDJ activity and the associated pro-apoptotic processes may be linked to the high degree of sensitivity in the production of these cells seen during chemotherapy treatment.…”

Combined single-cell gene and isoform expression analysis in haematopoietic stem and progenitor cells

“…Following the observation that IgK transcripts were upregulated in the aged LT-HSC population, and indeed throughout the myeloid progenitor (Fig 2M), we used the long read data to determine that the IgK arising from the LT-HSC population in aged mice consisted not just of "germline" IgK, as previously reported 12 , but fully VDJ-recombined transcripts (Fig 2N, Supplementary Fig 3). While unprecedented, there is an increasing body of evidence that the expression of recombined Ig molecules in non-lymphoid cells is possible [19][20][21] , often in age-related diseases such as acute myeloid leukemia 22 .…”