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An issue that is commonly addressed in our submissions is unclear polyglobulia/erythrocytoses after exclusion of a JAK2 mutation, the marker lesion for polycythemia vera (PV). However, PV is only rarely diagnosed in JAK2 negative patients upon bone marrow histology.
If, after molecular genetic and histological exclusion of PV in the clinical and anamnestic context, there is no appropriate cause for a possibly secondary polyglobulia, the case remains unclarified. Regarding a differential diagnosis, we have so far been able to offer a molecular genetic clarification of a familial erythrocytosis, but this diagnosis can also only be extremely rarely confirmed.
The publication by Wouters et al. in Blood Advances (2020), in which a subcohort of 133 individuals with erythrocytosis (according to the stricter WHO criteria of 2008, i.e. with Hb > 18.5 g/dl or Hct > 52% in men or with Hb > 16.5 g/dl or Hct > 48% in women) was investigated from the large-scale population-based Dutch lifeline cohort. In the molecular genetic investigation, evidence of clonal hematopoiesis was found in 51 of 133 individuals (38%). A JAK2 mutation characteristic of polycythemia vera was present, however, in only 7 of 133 (5.3%) cases. Other mutated genes were mainly BCOR/BCORL1 (16%), DNMT3A (14%), TP53 (10%), TET2 (6%) and ASXL1 (5%), and to a lesser extent also RUNX1, CALR, CSF3R, SF3B1, EZH2 and NRAS. While cases with a JAK2 mutation all also showed accompanying leukocytosis or thrombocytosis, all other mutations were also found in cases with isolated erythrocytosis. The common feature of the entire subcohort of clonal erythrocytoses was an association with increased cardiovascular mortality (hazard ratio 2.2).
On the basis of these new data and the demonstrated clinical relevance, an expanded molecular genetic clarification of JAK2-negative erythrocytoses appears promising. This is why we have expanded our range of examinations to include a new panel “JAK-negative erythrocytosis/polyglobulia” (see our current Request form or our digital order entry system (German language)).
Incidentally: another addition to our range of examinations concerns NK cell neoplasias. It is difficult to distinguish these from reactive changes. In around 30% of cases, this is achieved by detecting a mutation in a gene involved in the JAK/STAT signaling pathway (especially STAT3). From our research cohort of 5,500 genomes, a previously unknown mutation in the CCL22 gene was detected in the 63 cases with NK cell neoplasias examined at a rate of 22% (exclusively in STAT3-unmutated cases), the functional relevance of which might then be demonstrated in the murine model. These new findings were raised in collaboration with Charles Mullighan’s group at St. Jude Children’s Research Hospital in Memphis. A manuscript is currently undergoing peer review.