Somatic JAK2 mutations and their tumor phenotypes.

Activating JAK2 mutations can arise from chromosomal translocations or point mutations/deletions/insertions. The former result in JAK2 fusion proteins that always involve the JAK2 kinase domain (JH1), in association with an oligomerization domain from one of several partner proteins, which promotes constitutive JAK2 phosphorylation and signal activation. Tumor phenotypes associated with JAK2 fusion proteins include both myeloid and lymphoid neoplasms with a certain degree of phenotypic specificity (see figure): ETV6-JAK2 [t(9;12)(p24;p13)] has been associated with T or B acute lymphoblastic leukemia (T-ALL or B-ALL, respectively); PCM1-JAK2 [t(8;9)(p22; p24)] with chronic eosinophilic leukemia and atypical chronic myeloid leukemia (aCML); BCR-JAK2 [t(9;22)(p24;q11.2)] with aCML and B-ALL; PAX5-JAK2 [inv(9)(p13;p24); t(9;9)(p13;p24); del(9)(p13p24)] with B-ALL; SSBP2-JAK2 [t(5;9)(q14.1;p24.1)] with B-ALL; STRN3-JAK2 [t(9;14)(p24;q12)] with B-ALL; and SEC31A-JAK2 [t(4;9)(q21;p24)] with HL. B-ALL has also been associated with JAK2 point mutations/deletions/insertions, involving the JH2 pseudokinase domain; these include a JAK2 exon 14 mutation (L611S) reported in a single case of B-ALL and recurrent JAK2 exon 16 mutations seen in ;18% of patients with DS-associated B-ALL. The latter always affect the arginine 683 residue (eg, R683G, R683S, and DIREED), and some of these mutations have been shown to induce JAK-Stat activation and cytokine-independent growth. Interestingly, JAK2DIREED bone marrow transplant assays inmicedisplayedaphenotype similar to that seen with JAK2V617F, suggesting a crucial role for the DS-associated trisomy 21 in directing the oncogenic activity to B-lymphoid rather than myeloid cells. The myeloproliferative neoplasm–associated JAK2V617F is the prototype JAK2 point mutation and involves the JH2 pseudokinase domain (exon 14). JAK2V617F is closely associated with PV, essential thrombocythemia, primary myelofibrosis, and refractory anemia with ring sideroblasts and thrombocytosis, with respective mutational frequencies of;98%, 50%, 60%, and 40%, respectively. The phenotypic diversity seen with JAK2V617F has been attributed to differences in mutant allele burden, presence of other coexisting mutations, and the order and stem cell level of mutation acquisition. Conversely, the PV phenotype has infrequently been associated with other mutations, including JAK2 exon 12 mutations. JAK2 exon 12 mutations were first described by Scott et al in 2007 and shown to account for the majority of patients with JAK2V617F-negative PV.Unlike the casewith JAK2V617F, which is a single nucleotide alteration, multiple JAK2 exon 12 mutations, often heterozygote, have been described and include nucleotide substitutions, deletions, or duplications; the most frequent were N542E543del, E543-D544del, F537-K539delinsL, K539L, and R541-E543delinsK. These mutations also involve the JH2 pseudokinase domain adjacent to its border with the JH3 domain, spanning residues 536 to 547. Compared with PV patients with JAK2V617F, those with JAK2 exon 12 mutations were younger and displayed higher hemoglobin levels, primarily erythroid proliferation, absence of bone marrow tri-lineage hyperplasia, and lower incidence of leukocytosis or thrombocytosis; however, survival and rate of disease complications were reported to be similarly affected by the 2 mutation variants. The abovementioned specificity of JAK2 exon 12 mutations to PV and, in particular, to the erythrocytosis phenotype, has been recapitulated in animalmodels. In their original description, Scott et al used JAK2K539L retroviral mouse models and induced marked erythrocytosis, which was more pronounced thanwas seen in JAK2V617Fmice; in contrast, although leukocytosis accompanied the erythrocytosis phenotype in both instances, its degree was significantly higher in JAK2V617F mice. The approach taken by Grisouard et al used JAK2-N542-E543del transgenic mice and generated an even more erythroidspecific phenotype, without leukocytosis, thrombocytosis, or myelofibrosis. Multiple factors might have contributed to the overlapping but apparently distinct phenotypes observed between the JAK2K539L and JAK2-N542-E543del mice, including the different strategies of genetic engineering applied in constructing the animal