Selective JAK2/ABL dual inhibition therapy effectively eliminates TKI-insensitive CML stem/progenitor cells

Abstract

Imatinib Mesylate (IM) and other tyrosine kinase inhibitor (TKI) therapies have had a major impact on the treatment of chronic myeloid leukemia (CML). However, TKI monotherapy is not curative, with relapse and persistence of leukemic stem cells (LSCs) remaining a challenge. We have recently identified an AHI-1-BCR-ABL-JAK2 protein complex that contributes to the transforming activity of BCR-ABL and IM-resistance in CML stem/progenitor cells. JAK2 thus emerges as an attractive target for improved therapies, but off-target effects of newly developed JAK2 inhibitors on normal hematopoietic cells remain a concern. We have examined the biological effects of a highly selective, orally bioavailable JAK2 inhibitor, BMS-911543, in combination with TKIs on CD34+ treatment-naïve IM-nonresponder cells. Combination therapy reduces JAK2/STAT5 and CRKL activities, induces apoptosis, inhibits proliferation and colony growth, and eliminates CML LSCs in vitro. Importantly, BMS-911543 selectively targets CML stem/progenitor cells while sparing healthy stem/progenitor cells. Oral BMS-911543 combined with the potent TKI dasatinib more effectively eliminates infiltrated leukemic cells in hematopoietic tissues than TKI monotherapy and enhances survival of leukemic mice. Dual targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may consequently lead to more effective disease eradication, especially in patients at high risk of TKI resistance and disease progression.

Stellettin B induces apoptosis in human chronic myeloid leukemia cells via targeting PI3K and Stat5

“…While Imatinib has highly improved the clinical therapy of CML, resistance remains a barrier to better patient outcomes [ 3 , 25 ]. Drug combination with lower doses might improve the therapeutic index while keeping low toxicity [ 26 ].…”

“…Bcr-Abl inhibitors like Imatinib, Nilotinib and Dasatinib, highly improved the clinical therapy of CML in the past years. However, drug resistance, early relapse and persistence of leukemic stem cells led to the limited outcome of Bcr-Abl inhibitor monotherapy [ 3 ]. Therefore, discovery of novel agent is still urgent for CML treatment.…”

Cellular and Molecular Networks in Chronic Myeloid Leukemia: The Leukemic Stem, Progenitor and Stromal Cell Interplay

“…AHI-1 interacts with JAK2 and BCR-ABL1 to confer TKI resistance [129]. Similar conclusions were drawn using JAK2 and β-catenin inhibitors [128, 138-141], although a recent study with JAK2 null mice [142] argues against JAK2 requirement for BCR-ABL1 leukemogenesis.…”

Update on emerging treatments for chronic myeloid leukemia

“…The observations on the relevance of JAK2/STAT5 in BCR-ABL signaling revealed challenging therapeutic implications due to the clinical availability of specific JAK2 inhibitors. In line with these considerations, several reports have described JAK2 inhibitors efficacy in CML murine models and cellular models [90,93]. Clinical trials are now recruiting patients to assess the efficacy of JAK2 inhibitors, and in particular ruxolitinib, in combination with TKI inhibitors to target CML stem cells (NCT01751425 and NCT01914484 clinical trials); a different JAK2 inhibitor, TC-02 citrate, is also being tested as a single agent in CML blast phase (NCT01204164 , Table 3).…”