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Friday, December 02, 2022

Biologists discover gene deletion behind abnormality in blood cancer cells

The mystery is being solved as to why the control centers, or nuclei, of some blood cancer cells are characteristically asymmetrical.

These new research findings provide clues on the origin and progression of these cancers, and may suggest ways to diagnose and treat some leukemias at an earlier stage.

These squeezed-in-the-middle nuclei, which look like pin-nés glasses, are called Pelger–Huet anomalies. They were first observed under a microscope in 1928. Checking for this cellular aberration has helped clinical laboratories diagnose leukemia and myelodysplastic syndrome, a disease of the blood-forming cells in the bone marrow.

Although this structural change inside blood cells indicates potential cancer, until a recent study, no one knew what caused it.

In the journal Cell Stem Cells, cancer biologists report the discovery of a genetic mutation behind this cell abnormality.

The primary diagnosis of many cancers, even in the era of genomic medicine, remains focused on the appearance of cells under the microscope.”


Dr. Sergei Daulatov, Associate Professor of Medicine, Department of Hematology, University of Washington School of Medicine

Dr. Sergei Daulatov is the senior investigator of the recent gene study, a collaborative work between several institutions.

The Pap smear, he said, is just one example of a cancer test that looks for irregularly shaped nuclei in a patient’s cells.

One of Dolatov’s own research interests is in malignancies of infection-fighting white blood cells called neutrophils. He and his team wanted to get to the molecular root of these cancers. They assumed that something was lurking in the genome of a more primitive progenitor, or stem cells, that go on to form the blood cell lineage.

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What determines the fate of these progenitor cells that lead to the emergence of cancer cells instead of normal neutrophils? While they are still in their multipotent state and capable of giving rise to any of a variety of blood cell categories, the progenitor cells for neutrophils, red blood cells or platelets are called myeloid cells.

The myeloid cells themselves can sometimes show abnormal, pre-cancerous changes. The researchers of this recent study were able to suspect a loss of nuclear lamin B1 encoded on chromosome 5q. It is often removed in the cells examined from abnormally growing myeloid tissue. Evidence from this study suggests that this loss is a defect in misshapen nuclei.

“Lamins are proteins that line the inside of the nucleus, and are mutated in inherited disorders — the well-known Progeria, a disorder of accelerated aging,” Dolatov explained. Lamin protein production is also often down-regulated in cancer.

“We showed that loss of nuclear Lamin B1 induces defects in nuclear morphology and human hematopoietic [blood-forming] stem cells associated with lethality,” note the researchers.

His group elaborated that lamin B1 deficiency alters genome organization. This in turn caused an expansion of blood-forming stem cells, a bias toward them to become myeloid, genome instability due to defective DNA damage repair, and other problems that set the stage for cancer.

They also showed that abnormal nuclei in cells of myeloid pre-cancerous growth in patients were associated with deletions in chromosome 5q spanning the lamin 1B1 region.

According to the researchers, the loss of lamin B1 was both necessary and sufficient to cause the Pelger–Huet anomalies. The scientists were able to link this unusual nuclear shape with progenitor and blood-forming stem cell fate determination through the organization of the genome.

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According to the researchers, the study also implicated nuclear lamin B1 as a master regulator of cell fate specification in blood-forming stem cells, genome integrity and nuclear morphology.

Summarizing the recent finding, Doulatov said, “We show that lamin B1 deletion causes alterations in stem cell function, nuclear size and leukemia progression. Our research detects lamin mutations in cancer and demonstrates that These mutations are responsible for the oddly shaped nucleus that have helped and puzzled pathologists over the past century to identify cancers.”

The latest genomic findings and their consequences for abrupt changes in blood-forming cells could be important in the future of leukemia care. The presence of these changes, the researchers said, could be an early cancer biomarker, the detection of which could allow earlier diagnosis and treatment of leukemia.

The research was supported by a Discovery Grant from the CUNY Foundation as well as grants from the National Heart, Lung and Blood Institute at the National Institutes of Health (Ro1 HL151651, R21 HL139864, R01 HL031823), NIH New Innovator Award (DP2 HL147126). ), Evans MDS Discovery Research Grant, American Society of Hematology Scholar Award, T32 Hematology Training Grant, National Cancer Center (P30CA015704) and Seattle Translational Tumor Research.

Source:

Journal Reference:

Reilly, A., and others. (2022) Deletion of lamin B1 in myeloid neoplasms causes nuclear anomaly and altered hematopoietic stem cell function. cell stem cells. doi.org/10.1016/j.stem.2022.02.010.

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