Editorial for Leukemia Research

In this issue of Leukemia Research, Veselovska et al., present an important study of pediatric essential thrombocythemia (ET) from the Czech Republic. Pediatric ET is a rare disorder that has not been well characterized. Thus, this study of 12 unrelated ET children and one individual with thrombocytosis and a family history of ET is especially valuable. When tested by allele specific PCR, detectable JAK2V617F mutation was not found in peripheral blood leukocytes, platelets or granulocytes and clonal hematopoiesis (detected by differential methylation of X-chromosome alleles) was only seen in one female of seven tested. Eight of the 12 ET patients demonstrated erythropoietin (Epo) hypersensitivity and endogenous erythroid colonies (EEC) were noted in 5 of the 12 ET patients. The patient with thrombocytosis and a family history of ET also demonstrated rare EECs. The investigators performed genotyping on these EECs, with a small minority containing the JAK2V617F mutation. Since JAK2V617F mutation can by mitotic recombination undergo uniparenteral disomy¹, a mixture of colonies bearing homozygous, heterozygous, and wild JAK2 alleles exist. It was suggested by Green’s laboratory that homozygosity of some erythroid progenitors is seen exclusively in PV and not in ET². However, these data have been challenged by multiple groups³ including ours⁴. As seen in Table 2 in the article, one ET child demonstrated one JAK2V617F homozygous EEC and one JAK2V617F heterozygous EEC; one patient demonstrated a single heterozygous EEC; and the patient with thrombocytosis and a family history of ET had one homozygous EEC with two wild-type colonies. This article makes several other important observations and raises important questions for the future.

First, this is a relatively large clinical description of pediatric ET. It suggests an incidence of 1.1/million children/year in the Czech Republic. No thrombosis or major bleeding was seen with a median follow up of 42 months, underlying an apparent benign course for this disorder during childhood.

Second, the presence of JAK2V617F containing colonies may support other evolving literature suggesting that homozygosity of this mutation is not limited to polycythemia vera (PV)³. This is in contrast to a frequently cited early study in patients with PV and ET², although in that study two ET patients developed homozygous cells after polycythemic transformation. As has been demonstrated in PV⁵, the presence of the homozygous mutation in patients with ET may portend a more aggressive clinical course⁶. As the authors explore in their discussion, the detection of this mutation in EECs, but not in the circulating peripheral blood cells, suggests that the JAK2V617F containing subclones are rare in these patients and below the level of PCR detection. Additionally, or perhaps alternatively, the culture conditions without the addition of Epo may have favored the JAK2V617F colonies. This would correlate with previously reported data from polycythemia vera showing that, in vitro, non-JAK2V617F cells are favored in the presence of Epo⁷, supported by the fact that no JAK2V617F colonies were seen in this study in Epo dependent BFU-E. Translation research efforts are ongoing to discover if supplemental erythropoietin can reduce or eliminate the JAK2V617F clone in patients with myeloproliferative disorders.

Third, the diagnostic and prognostic significance of EECs appearing in pediatric ET remains to be seen. As the authors discuss, existing data suggest a strong likelihood that adults who have EECs will eventually develop polycythemia vera^8,9. The presence of EECs is frequently used as a clinical distinction in adults when assigning a diagnosis to a patient with an apparent myeloproliferative disorder. Whether or not this is true in children will have to be elucidated by further longitudinal studies.

In summary, we applaud the efforts of the authors to further our understanding of a rare disorder. It is clear that the development of diagnostic and prognostic algorithms in the myeloproliferative disorders, in both children and adults, will continue to be a fluid process as more knowledge is gained.