Blood cancer researchers find genetic puzzle piece


Research on neoplasms like Chronic Myeloid Leukemia (CML) finds another genetic element towards diagnosis.

The new element is the gene for calreticulin (CALR), the investigators reported at the annual meeting of the American Society of Hematology and online in the New England Journal of Medicine.

The finding should help in the diagnosis of myeloproliferative neoplasms, and especially essential thrombocythemia and primary myelofibrosis, according to researchers led by Robert Kralovics, PhD, of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna, and Anthony Green, FRCPath, of the Cambridge Institute for Medical Research in Cambridge, England.

The myeloproliferative neoplasms are clonal hematopoietic disorders that involve expansion of myeloid cells. Chronic myeloid leukemia (CML) is the most common, along with polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

While the genetic basis for CML -- the so-called Philadelphia chromosome -- has been known for several decades, it was only recently that mutations in the Janus kinase 2 gene (JAK2) were shown to be involved in the pathogenesis of some of the other disorders.

But in many patients, JAK2 is not mutated (nor is another causative gene, MPL) and the genetic basis of their disease has remained obscure, according to Ross Levine, MD, of Memorial Sloan-Kettering Cancer Center in New York City.

Writing in an editorial accompanying the online reports by Kralovics and Green, Levine argued that the studies "provide strong genetic evidence" linking CALR mutations to disease in patients without JAK2 mutations.

But it remains unclear exactly how the CALR mutations cause disease, he noted -- the gene codes for calreticulin, an endoplasmic reticulum chaperone protein that has not previously been linked with malignancies.

Nonetheless, the research has helped to "solve this puzzle" of how several disorders can arise in the absence of the known causative mutations, he wrote.

Both groups used so-called exome sequencing -- looking just at the DNA that codes for proteins -- in order to find somatic mutations that might be linked with myeloproliferative neoplasms.

Kralovics and colleagues began by finding such changes in six patients with primary myelofibrosis but without mutations in JAK2 or MPL, which has also been implicated in the pathogenesis of the disease.

Then they re-sequenced CALR in 1,107 samples and found that -- in essential thrombocythemia and primary myelofibrosis -- patients with CALR mutations did not have mutations in JAK2 and MPL and vice versa.

Among patients with those conditions and wild-type JAK2 or MPL, 67% of those with essential thrombocythemia and 88% of those with primary myelofibrosis had CALR mutations, they found.

Using slightly different methods, Green and colleagues found much the same thing -- somatic CALR mutations showed up in 70% to 84% of samples of myeloproliferative neoplasms with non-mutated JAK2.

Again, they showed that CALR and JAK2 or MPL mutations were mutually exclusive.

Various CALR mutations were found, but all resulted in a frame-shift in exon 9 of the gene, both groups reported.

The investigators also noted that patients with CALR mutations tended to present with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2.

Because the mutations can be detected in peripheral blood, Green and colleagues concluded they have the potential to become "a diagnostic tool in the same way that tests for JAK2 mutations have simplified and improved the accuracy of diagnosis of patients with myeloproliferative neoplasms worldwide."


Source: MedPage Today:

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