JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo

Paolo Gallipoli, Amy Cook, Susan Rhodes, Lisa Hopcroft, Helen Wheadon, Anthony D. Whetton, Heather G. Jørgensen, Ravi Bhatia and Tessa L. Holyoake

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  • RE: JAK inhibitors along with TKIs can eradicate CML lineage negative cells
    • Subramaniam Agatheeswaran, Ph.D. Student Institute of Life Sciences
    • Other Contributors:
      • Soumen Chakraborty, Principal Investigator

    In spite of the success with TKIs, residual BCR-ABL positive cells were found in majority of the patients. Studies on CML persistency found that BCR-ABL positive CD34+ cells, residing in the bone marrow (1), are resistant to the TKIs and hence mechanisms responsible for their survival and due elimination should be studied extensively. In this regard the article by Paolo Gallipoli et al., 2014 shows promising results where clinical JAK2 inhibitor (ruxolitinib) was used along with nilotinib to kill the BCR-ABL positive stem and progenitor cells. But a recent study states that a combination of ruxolitinib and imatinib fails to increase the cell death in BCR-ABL transduced LSK cells and may not be beneficial (3). We have used imatinib along with JAK inhibitor 1 to evaluate the significance of JAK2 kinase inhibition in eliminating the CML lineage negative (lin(-)) cells.

    We purified CML lin(-) cells from the bone marrow of naive CML cases using CML debulking kit (Stem cell technology, Canada) and found that approximately 80% of the lin(-) cells are positive for CD34 marker (Fig 1A). We found that imatinib efficiently blocks the BCR-ABL kinase activity (Fig 1B) but fails to eliminate the CML lin(-) cells in an in vitro culture system when supplemented with cytokines, as found by others (4-6). It has been reported in numerous studies that stromal cells secrete certain growth factors which are responsible for the activation of JAK-STAT pathway apart from BCR-ABL and...

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    Conflict of Interest:
    None declared.