Microbiomarkers with big impact in CLL

In this issue of Blood, Ferrajoli et al examined the microRNA (miRNA) miR-155 as a biomarker for chronic lymphocytic leukemia (CLL).¹  Increased expression of cellular and plasma miR-155 was observed in patients with CLL and correlated with poor survival and therapeutic response, suggesting that plasma-based noncoding RNA biomarkers may one day be a reality.

B-cell CLL is the most common type of leukemia in adults and accounts for approximately one-third of all leukemias in the United States. CLL is a heterogeneous disease that stems from a clonal proliferation of CD5-positive B lymphocytes accumulating in the blood, bone marrow, lymph nodes, and to some extent, spleen and liver. CLL stems from a combination of genetic (chromosomal abnormalities, gene mutations) as well as epigenetic (altered microRNA expression, DNA methylation) modifications. A major goal of CLL research is to more completely understand the molecular basis of the disease and to have predictors available for the response to treatment.

Monoclonal B-cell lymphocytosis (MBL) is a disorder of hyperproliferative B cells with molecular features that are similar to CLL. Individuals who are diagnosed with MBL have a much lower neoplastic B-cell count compared with those with CLL. Although 1% to 2% of patients with MBL will develop CLL requiring treatment,²  a direct progression of MBL to CLL is controversial.³ 

For years, researchers have focused on alterations to DNA and protein as evidence of CLL progression. A number of studies, including one published in this issue of Blood,¹  suggest that small, noncoding miRNA may offer clues to the etiology and prognosis of this disease. Ferrajoli et al, in George Calin’s laboratory, examined the expression of the miRNA miR-155 in large discovery and validation cohorts of patients with CLL and MBL. miR-155 has previously been shown to be highly expressed in patients with CLL,^4,5  and transgenic mice overexpressing miR-155 develop a B cell-type of leukemia.⁶  However a link between miR-155 and CLL prognosis has been missing until now.

miR-155 expression was higher in MBL, and even more so in CLL, compared with MBL and normal B cells (see figure). High miR-155 expression was seen in patients with poor overall survival and in patients who were poor responders to standard therapy. Although additional validation studies are needed, the data suggest that knowledge of circulating miRNAs such as miR-155 may someday be used to predict which patients with MBL go on to develop overt CLL.

Importantly, the investigators looked at several types of specimens, including CLL cells and plasma from patients with CLL. Plasma miR-155 was as effective a biomarker as miR-155 isolated from cells. Plasma is easier to work with for routine clinical biomarker screening than cellular material. Plasma has also been shown in a number of studies (reviewed in Cortez et al⁷ ) to contain tiny microvesicles that package miRNA and other biomolecules. Although the investigators only analyzed a small number of samples, the work demonstrated that microvesicles isolated from the plasma of patients with CLL also contained miR-155. This raises important questions such as what the purpose of miR-155 in secreted microvesicles is, and can they act as hormones, as suggested.⁷ 

Having a plasma-based biomarker to predict which patients will respond to therapy is a Holy Grail of cancer therapeutics. Although future studies will require multicenter trials to evaluate the predictive value of miR-155, the results presented by Ferrajoli et al are very encouraging.

Conflict-of-interest disclosure: The author declares no competing financial interests.