Study in Blood Identifies Novel Mutations in Triple-Negative Myeloproliferative Neoplasms

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Using whole-exome sequencing and evaluating germline mutations, researchers have discovered novel mutations in several genes among patients with essential thrombocythemia and primary myelofibrosis, which could influence the treatment they receive.

A study published in Blood shares the discovery of novel mutations in triple-negative myeloproliferative neoplasms through whole-exome sequencing (WES).

Essential thrombocythemia (ET), polycythemia vera, and primary myelofibrosis (PMF) are chronic diseases caused by somatic mutations of differentiated myeloid cells. In most of the cases, mutational genes are identified as either Janus kinase 2 (JAK2)-V617F, exon 9 of calreticulin (CALR), or exon 10 of myeloproliferative leukemia protein (MPL). However, in a small population of patients with ET or PMF (<10%), none of these mutations account for the disease, classifying this group of patients as triple negative. In their study, Feenstra et al sought to identify what caused the mutation in triple-negative cases by evaluating WES and germline mutations.

Seventy-nine patients with either ET or PMF were included in the study with no JAK2, MPL, and CALR mutations upon analysis. WES was performed in 8 cases of ET and PMF. In 3 of the 8 patients (2 diagnosed PMF and 1 ET), somatic mutations were identified by WES, with relevant malignancies consisting of CBL, TET2, ASXL1, SRSF2, and MPL S204P. No new recurrent somatic mutations were detected in any of the 8 patients. In the other 5 patients, no single somatic mutation was detected by WES, and instead they were analyzed for presence of germline mutations.


Read more about causes and treatment options for myeloproliferative disorders.

In 1 patient with PMF, the investigators found a germline mutation in MPL V285E, and in another patient with ET who had somatic mutations, they found a germline variant in JAK2 G571S. Granulocyte DNA samples were also analyzed for chromosomal copy alternations and uniparental disomies (UPD). Among the 8 patients, 1 patient with PMF carrying the germline MPL V285E had an UPD of chromosome 6p, while 1 patient with ET carrying the germline JAK2 G571S had a gain on chromosome 4q.

Mutations outside of exon 10 of MPL were identified in 7 of 69 cases, and germline mutation variants of JAK2 were found in 5 of 57 cases. Somatic mutations for MPL were detected at T119I, S204F, S204P, and E230G, and germline mutations at V285E and R321W. Germline mutations of JAK2 occurred at positions G335D, G571S, V625F, and F556V. All MPL mutations demonstrated an activation of JAK signal transducer and activator of transcription 5 (STAT5) signaling. JAK2 V625F and F556V also represented gain of function mutation, leading to an increased activation of JAK STAT5. Together, these mutations represented 18.9% of all triple-negative cases.

Triple-negative status of any of these chronic diseases is associated with decreased overall and progression-free survival, potentially due to the lack of mutation knowledge. In this study, WES and other genomic sequencing tests searched for somatic and germline mutations that could help categorize these patients. As more data are collected on which mutations drive the disease, through RNA sequencing or other approaches, clinicians may have a better understanding and subsequently have better ways to treat these patients.


Feenstra JD, Nivarthi H, Gisslinger H, et al. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood. 2016;127(3):325-332. doi: 10.1182/blood-2015-07-661835.