Detection of a new JAK2 D620E mutation in addition to V617F in a patient with polycythemia vera

JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials

“…In general, the novel allele, when present, is found in MPD cases that are JAK2V617F negative (for example, MPLW515L or MPLW515K), 39 although in rare cases, these alleles may occur in conjunction with JAK2V617F (for example, JAK2D620E, MPLW515L/K). [40][41][42] A similar co-occurrence of BCR-ABL and JAK2V617F alleles has also been described in MPD patientsFthe clinical phenotype in these patients (that is, chronic myeloid leukemia (CML) versus PV, for instance) may depend on which mutant clone is dominant. 43,44 The MPLW515 mutations are restricted to patients with JAK2V617F-negative PMF (B10%) or JAK2V617F-negative ET (1%).…”

TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations

“…In general, the novel allele appears to substitute for JAK2V617F (for example, JAK2 exon 12 mutations, JAK2DIREED), 4,6 although in some cases, such alleles act in conjunction with JAK2V617F (for example, JAK2D620E, MPLW515L/K). 3,16 These mutant alleles effectively converge upon JAK2, leading to constitutive autophosphorylation of this kinase. These observations raise the possibility that most, if not all, MPD patients harbor mutations (some yet to be identified) that potentially serve as a molecular target for a selective JAK2 inhibitor.…”

“…2 Dysregulated JAK-STAT signaling may be important in JAK2V617F-negative MPD as well, in that other activating JAK2 alleles have been identified in these patients, including JAK2 exon 12 mutations, JAK2D620E, JAK2DIREED, in addition to activating mutations in MPL at position W515. [3][4][5][6] Expression of JAK2V617F in vivo in a murine bone marrow transplant assay results in a phenotype resembling PV; 7,8 in contrast, MPLW515L expression in a similar assay results in a PMF-like phenotype. 9 Inhibition of JAK2 with small molecule 'tool' compounds that lack potential for clinical development, and that are not selective among JAK family members, induce apoptotic cell death in hematopoietic cell lines transformed either with JAK2V617F 10 or with MPLW515L, 9 and, similarly, may decrease the hematocrit in mouse models of JAK2V617F-induced disease.…”

Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms

“…JAK2V617F, JAK2 exon 12 mutations) in virtually all patients with PV. [8][9][10][11][12][13][40][41][42][43][44][45] Because JAK2V617F is myeloid neoplasm-specific and not found in other causes of polycythemia, [46][47][48] it has lent itself to being a sensitive diagnostic marker for PV. 44 However, in the context of myeloid neoplasms, JAK2V617F is not specific for PV and is found in approximately 50% of patients with ET, [49][50][51][52][53][54]56 or RARS-T, [57][58][59][60][61] and at a lesser frequency in other myeloid neoplasms, [62][63][64][65][66][67][68][69][70] but not in lymphoid tumors.…”