In a new study, researchers characterized changes in myeloid neoplasms associated with the deletion of the lamin B1 (LMNB1) gene and described their findings in a report in the journal Cell Stem Cell.
An alteration to nuclear morphology that is frequently seen in myeloid neoplasms is the Pelger-Huët anomaly (PHA). Abnormal neutrophils with PHA, for example, feature nuclei with abnormal lobulation, 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 gene is located on chromosome 5q. This gene encodes a protein that is associated with the structural integrity of the nuclear envelope, and deletion of chromosome 5q (del5q) is common in myeloid neoplasms. The researchers performing the study set out to determine any associations between deletion of LMNB1 and acquired PHA.
The researchers initially evaluated differences in LMNB1 expression between normal hematopoietic stem cells (HSPCs) 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 comparisons. The researchers performed multiple analyses in varied cell types in order to evaluate LMNB1 expression and the effects of disrupting the expression of this gene.
Cells associated with AML showed reduced expression of LMNB1 RNA, compared with 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 TCGA, those with del5q showed 42% less expression of LMNB1 than patients without del5q did.
The researchers also performed LMNB1 knockdowns in HSPCs to observe effects of expression of this gene on hematopoiesis. Overall, compared with normal HSPC patterns, decreased expression of LMNB1 was associated with a greater proportion of cells of myeloid lineage, while lymphoid differentiation became impaired.
Additionally, loss of LMNB1 expression was associated with the appearance of PHA-type nuclear changes in neutrophils. Genomic instability was also greater in cells that were deficient in LMNB1 expression due to disrupted DNA damage repair in these cells. Chromatin spatial organization was also altered in both HSPCs and neutrophils with decreased LMNB1 expression.
“We demonstrate that abnormal nuclear morphology is causally linked with myeloid-biased fate determination and loss of genome integrity via reduced LMNB1 gene dosage,” the researchers wrote in their report. “As LMNB1 loss is frequent in MDS/AML and other cancers, our findings help explain why nuclear dysmorphology is pervasive in myeloid malignancies and possibly across cancers.”
Reilly A, Creamer JP, Stewart S, et al. Lamin B1 deletion in myeloid neoplasms causes nuclear anomaly and altered hematopoietic stem cell function. Cell Stem Cell. 2022;29(4):577-592.e8. doi:10.1016/j.stem.2022.02.010