Properties of Chronic Myeloid Leukemia Stem Cells: Strategy Based on the Kinetics during Treatment with ABL-Tyrosine Kinase Inhibitors

Chronic Myeloid Leukemia (CML) is effectively treated with Tyrosine Kinase Inhibitors (TKI) such as Imatinib Mesylate (IM) targeted against BCR-ABL, however, several mathematical models and ex vivo-examinations suggested that IM does not eradicate CML stem cells. We previously reported the investigation of residual CML diseases during TKI treatment using FACS-sorting and quantitative RT-PCR of BCRABL among each population; total mononuclear cells, hematopoietic stem cells, and myeloid progenitors. Our observations were supportive of the mathematical model that consists of the initial rapid α-slope and the consequent β-slope correspondent to kinetics of residual cells. The observations also implied that the second-generation of ABL-tyrosine kinase inhibitors (2nd TKIs), dasatinib or nilotinib therapy can be more promising approach for efficient reduction of the CML stem cells.Moreover, we need to develop the evaluation method of the residual CML stem cells to establish rational TKI-cessation strategies in CML. ProPerties of ChroniC Myeloid leukeMia steM Cells Chronic Myeloid Leukemia (CML) is a clonal myelo proliferative disorder that is characterized by the presence of a fusion oncogene, BCR-ABL, which encodes a protein with constitutive tyrosine kinase activity [1]. The mechanisms for TKI insensitivity of CML stem remains unclear; factors such as quiescence, high level of BCR-ABL expression, acquired mutations in the oncogene, and overexpression of membrane transporter proteins in these cells may play a role [2-4]. In the normal myelopoiesis is sustained through the life by the regulated proliferative and differentiation activity of a large pool of Hematopoietic Stem Cells (HSCs) (Figure 1A). Cells within hematopoietic hierarchy can be distinguished by their proliferative and differentiation activity which they display under conditions designed to optimally elicit these, either in vivo (where the most primitive cells are called long-term repopulating cells, LTRCs) or in vitro (as long-term culture-initiating cells, LTCICs and CFCs) [5,6]. Surface markers, such as CD34 and CD38 are differentially expresses upon differentiation, progenitors being mostly CD34+CD38+ and HSCs exclusively CD34+CD38-7. In patients with CML-Chronic Phase (CP), normal and leukemic cell population co-exist (Figure 1B) [1,4,8,9]. In the stem cell compartment, normal HSCs often outnumber the small numbers of their leukemic counterparts. However, current evidence suggests that the normal HSCs are outcompeted by the CML stem cells when these begin to proliferate and differentiate, which the CML stem cells also attempt more frequently due to their higher turnover and increased probability of differentiation. The autocrine secretion of IL-3 and Granulocyte colony stimulating factor (G-CSF) by primitive leukemic progenitors likely contributes to growth advantage of leukemic myeloid progenitors and mature cells in patients resulting in their dominance of peripheral blood and bone marrow of newly diagnosed CML patients with mature CML cells [6]. residual CMl stem cells during treatment with aBltyrosine kinase inhibitors The use of Tyrosine Kinase Inhibitors (TKI) such as Imatinib Mesylate (IM) targeted against BCR-ABL has proven successful in CML and long-term survival has become a reality [10,11]. However, several mathematical models and ex-vivo examinations suggested that imatinib (IM) therapy does not eradicate CML stem cells [3,8,12-14]. We previously reported a method for investigation of CML-CP cases during TKI treatment using Special Issue on future aspects of Chronic Myeloid leukemia treatment Central Minami (2014) Email: J Hematol Transfus 2(3): 1025 (2014) 2/4 Self-re newal ! Quies cence ! Differe ntiatio n " ��Proliferation ��IL-3 / G-CSF increased turn over and yield Leukemic myelopoiesis Self-renewal Quiescence Differentiation Non Leukemic myelopoiesis CML patient myelopoiesis LTRCs: Lin!34"38!� LTC-ICs: Lin!34"38!� CFCs: Lin!34"38"� [ A. Normal individual ] [ B. CML-CP patient ] Self-renewal Quiescence Differentiation LTRCs: Lin!34"38!� LTC-ICs: Lin!34"38!