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BGI, NCI Study Shows 29-Year Evolution of Multiple CLL Clones in Single Patient

NEW YORK (GenomeWeb) – A new study by researchers at BGI and the US National Cancer Institute reveals the pattern of chromosomal alterations in an individual chronic lymphocytic leukemia (CLL) patient observed over a 29-year period.

Published today in Nature Communications, the work shows complex changes in gene expression over time, with the disease evolving gradually during slow-growing phases, undergoing rapid changes after therapy, and showing expression changes involving cell proliferation, migration, differentiation,and immune response.

The patient described in the research was initially diagnosed with CLL in 1972 when she was 47 years old. She received chemotherapy with a cytotoxic agent called chlorambucil for the first time in the 16th year of her illness, again in year 22 through 23, and she died in 2001.

Samples were collected at different time points between the 8th and 28th year, and researchers ran SNP microarray analyses, whole genome bulk sequencing, and whole genome single-cell DNA/RNA sequencing with viably frozen lymphocytes.

The first testing showed one fundamental cell clone that was eliminated by the initial therapy with deletions at 13q14 and 6q, and an amplification at 12q.

A 2-MB deletion in 13q14 was detected in the early stage of illness, but between the first and second therapies a 12-MB homozygous deletion in 13q14 appeared. This deletion led to the loss of a tumor suppressor, RB1, and may have contributed to the deterioration of the patient’s condition, the authors suggested.

Using single-cell RNA-seq the study showed high FOS, JUN, and KLF4 expression initially, which emerged at the same time as the larger 13q14 deletion.

However, after a second course of therapy the cells developed a greater diversity of expression profiles, although during a short disease remission the expression patterns were again similar to those of early CLL. Signaling pathways, including B cell receptor, EGFR, ERKs, and NF-kappa B, also demonstrated expression changes with evolution of the disease.

The researchers used an algorithm called Monocle to analyze temporal changes in gene expression. Furthermore, "The frequent changes in copy number variation patterns over the 16 years following initial treatment indicates the cancer cells are highly adaptable," NCI's Michael Dean, a lead author of the study, said in a statement.

Although the study is limited because it involves only a single patient, the researchers noted that it is "the most detailed and extensive analysis of a single leukemia patient in terms of number of samples analyzed over time, using multiple DNA and RNA sequencing methods on bulk and single cells," adding that the disease stages can now be dissected and provide insights into tumor progression and evolution.

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