Deletion of the LMNB1 gene associated with altered nuclear structure in myeloid neoplasms
In a new study, researchers have characterized changes in myeloid neoplasms associated with deletion of lamin B1 (LMNB1) gene and described their findings in a report published in the journal Cell Stem Cell.
A frequently observed alteration in nuclear morphology in myeloid neoplasms is the Pelger-Huët anomaly (PHA). Abnormal neutrophils with PHA, for example, show abnormally lobulated nuclei, containing 1 or 2 lobes, rather than multiple lobes, in addition to coarse clumping of chromatin. An inherited form of PHA is associated with mutations in the lamin B receptor, while acquired PHA is found in myeloid neoplasms.
the LMNB1 The gene is located on chromosome 5q. This gene encodes a protein associated with structural integrity of the nuclear envelope, and deletion of chromosome 5q (del5q) is common in myeloid neoplasms. The researchers who conducted the study sought to determine any association between the suppression of LMNB1 and acquired PHA.
The researchers first assessed the differences in LMNB1 between normal hematopoietic stem cells (HSPC) and cells from patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Messenger RNA expression signatures found in The Cancer Genome Atlas (TCGA) were also used for comparison. The researchers performed several analyzes in various cell types to assess LMNB1 expression and the effects of disruption of expression of this gene.
AML-associated cells showed reduced expression of LMNB1 RNA, compared to expression in normal cells. A total of 14 patients with AML and del5q with data in TCGA all showed LMNB1 deletions. Additionally, among patients with AML in the TCGA, those with del5q showed 42% less expression of LMNB1 than patients without del5q.
The researchers also made LMNB1 knockdowns in HSPCs to observe the effects of the expression of this gene on hematopoiesis. Overall, compared to normal HSPC models, decreased expression of LMNB1 was associated with a greater proportion of myeloid lineage cells, while lymphoid differentiation was impaired.
Additionally, the loss of LMNB1 expression was associated with the appearance of PHA-like nuclear changes in neutrophils. Genomic instability was also greater in cells deficient in LMNB1 expression due to interrupted DNA damage repair in these cells. The spatial organization of chromatin was also altered in both HSPCs and neutrophils with a decrease LMNB1 expression.
“We demonstrate that abnormal nuclear morphology is causally related to biased myeloid fate determination and loss of genome integrity via reduced LMNB1 genetic assay,” the researchers wrote in their report. “Like LMNB1 loss is common in MDS/AML and other cancers, our results help explain why nuclear dysmorphology is ubiquitous in myeloid malignancies and perhaps in all cancers.
Reilly A, Creamer JP, Stewart S, et al. Deletion of lamin B1 in myeloid neoplasms causes nuclear abnormality and impaired hematopoietic stem cell function. Cell Stem Cell. 2022;29(4):577-592.e8. doi:10.1016/j.stem.2022.02.010