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TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients

Leukemia volume 22, pages 1790–1792 (2008)Cite this article

We previously reported that TG101209, a JAK2-selective small molecule inhibitor, inhibits ex vivo hematopoietic colony growth in the context of myeloproliferative disorder (MPD)-relevant JAK2V617F and MPLW515L/K mutations.1, 2 More recently, phase I testing in the clinic has started with a related compound, TG101348, for the treatment of myelofibrosis patients—currently, those with intermediate- or high-risk disease, relapsed/refractory disease or symptomatic splenomegaly are eligible to participate, irrespective of JAK2V617F mutation status. Two recent reports have shown TG101348 to be effective in treating a murine model of JAK2V617F-induced MPD and in inhibiting the engraftment of polycythemia vera (PV) progenitor cells in a mouse xenotransplant model, respectively.3, 4 Using leukemic cell lines and primary cells from MPD patients, we sought to address the following clinically relevant questions pertaining to TG101348 in the context of the aforementioned clinical trial: (i) is there a ‘therapeutic window’ vis-à-vis inhibition of normal hematopoietic progenitor cell growth? (ii) is the growth of mutation-harboring colonies selectively suppressed—is this effect equipotent in the presence and absence of exogenous erythropoietin (Epo) (that is, does Epo counteract the inhibitory effect of TG101348)? (iii) does the presence of JAK2 exon 12 mutations also confer sensitivity to inhibition with TG101348? and (iv) are MPD patients from whom mutations have not yet been identified as sensitive to JAK2 inhibition as patients with known mutations?

Cell proliferation was assessed using the XTT assay.1 The inhibitory effect of TG101348 on ex vivo hematopoietic colony growth was studied in 15 MPD patients (12 PV patients with JAK2V617F; one PV patient with an JAK2 exon 12 mutation (N542-E543del); one primary myelofibrosis (PMF) patient with MPLW515K; one PMF patient without identifiable mutation), and two healthy controls (Table 1). Peripheral blood samples were collected after informed consent and the mononuclear cell fraction was plated at a concentration of 3 × 105 per plate with and without erythropoietin, as described previously.1 TG101348 was added at the following concentrations: 0, 300, 600 and 1200 nM. Colonies were scored and isolated for individual genotyping on or around day 14. Genotyping for JAK2V617F and MPLW515K mutations was performed by PCR sequencing.5

Table 1 TG101348 effects on erythroid colony growth in MPD patients
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References

  1. Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia 2007; 21: 1658–1668.

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  4. Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell 2008 (in press).

  5. Lasho TL, Pardanani A, McClure RF, Mesa RA, Levine RL, Gilliland DG et al. Concurrent MPL515 and JAK2V617F mutations in myelofibrosis: chronology of clonal emergence and changes in mutant allele burden over time. Br J Haematol 2006; 135: 683–687.

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Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    T L Lasho, A Tefferi & A Pardanani

  2. TargeGen Inc., San Diego, CA, USA

    J D Hood

  3. Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, USA

    S Verstovsek

  4. Department of Medicine, Brigham and Women's Hospital and The Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    D G Gilliland

  5. Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA

    D G Gilliland

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  1. T L Lasho
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  2. A Tefferi
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  3. J D Hood
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  4. S Verstovsek
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  5. D G Gilliland
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  6. A Pardanani
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Correspondence to A Pardanani.

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Disclosures

John Hood is an employee and shareholder of TargeGen Inc. This work was supported by a research grant from TargeGen Inc. and from the Myeloproliferative Disorders Foundation, Chicago, IL, USA.

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Lasho, T., Tefferi, A., Hood, J. et al. TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia 22, 1790–1792 (2008). https://doi.org/10.1038/leu.2008.56

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