BCR-ABL1 is a secondary event after JAK2V617F in patients with polycythemia vera who develop chronic myeloid leukemia

To the editor:

Two patients with a history of JAK2V617F⁺ polycythemia vera (PV) without a family history of a myeloproliferative neoplasms developed chronic myeloid leukemia (CML) 12 and 18 years after their initial presentation. Only patient 1 received myelosuppressive therapy (hydroxyurea). To understand the relationship between the acquisition of JAK2V617F and BCR-ABL1, we performed genotypic analyses of hematopoietic progenitor cells (HPCs) assayed from these patients.

As shown in Figure 1A, all 48 hematopoietic colonies (HCs) cloned in semisolid medium from patient 1 were homozygous for JAK2V617F, and 4 of 48 (8%) HCs contained both JAK2V617F and BCR-ABL1. Each of the 33 HCs from patient 2 contained JAK2V617F, whereas the BCR-ABL1 fusion was identified in 18% of colonies heterozygous for JAK2V617F and in 58% colonies homozygous for JAK2V617F. JAK2 wild-type HCs were not identified even in the presence of a high concentration of erythropoietin in either patient. HCs with BCR-ABL1 without JAK2V617F were also not observed (Figure 1A).

Single-cell analyses were used to exclude the possibility that the coexistence of BCR-ABL1 fusion and JAK2V617F mutation in a single HC generated in semisolid medium might be the result of cells migrating from one colony to another. Clonal evolution can be inferred using such single-cell studies.^1,2  As shown in Figure 1B, the distribution of genotypes of the colonies cloned from a single CD34⁺ cell from these 2 patients was similar to that of HCs generated in semisolid medium. These studies suggest that the acquisition of BCR-ABL1 occurred after JAK2V617F and that the development of CML is a secondary event that may occur in either heterozygous (patient 2) or homozygous (patient 1) JAK2V617F⁺ HPCs.

Bocchia et al reported a similar patient with PV who developed CML in whom JAK2V617F and BCR-ABL coexisted in HPCs committed to multiple hematopoietic lineages.³  In contrast, Cambier et al provided evidence in another PV patient who developed CML that the PV and CML originated from distinct clones.⁴  Our findings indicate that both the JAK2V617F mutation and BCR-ABL1 can occur concurrently in both CFU-GM and BFU-E and that JAK2V617F occurs before the acquisition of BCR-ABL1.

The clinical phenotype of myeloproliferative neoplasms frequently evolves over time. Although this progression can be enhanced by the use of chemotherapeutic agents, it represents the natural clonal evolution of these malignancies. The development of CML in PV occurs much less frequently than myelofibrosis or acute myeloid leukemia, but should be considered in patients with PV who develop extreme leukocytosis. The contribution of BCR-ABL1 to disease progression appears to be greater than that of JAK2V617F, because these patients display a clinical phenotype that is consistent with CML rather than PV. These clinical observations represent an example of clonal evolution in which the initial genetic event is a mutation leading to the activation of a tyrosine kinase (JAK2), which is then followed by either a second genetic event leading to the acquisition of a fusion protein resulting in activation of another protein kinase (BCR-ABL1) or by homologous recombination resulting in JAK2V617F-homozygous HPCs that lack BCR-ABL1. Subsequently, the JAK2V617F-heterozygous HPCs with BCR-ABL1 can also undergo homologous recombination and become homozygous for JAK2V617F.