Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3

Insights into the stem cells of chronic myeloid leukemia

“…43 When similar measurements are applied to primitive CML cells, the overall trend is a pronounced increase in the proliferative activity of all cells detectable as CFCs 43 and some increase in the proliferative activity of LTC-ICs, regardless of their location in marrow or blood. 63 The autocrine IL-3/ granulocyte colony-stimulating factor mechanism documented to be active in virtually every proliferating primitive (CD34 þ ) CML cell 66,73 provides a candidate mechanistic explanation for both the increased cycling and viability of CML CFCs as both of these cytokines are known to stimulate these activities in normal CFCs. In addition, primitive CML cells show a reduced insensitivity to the specific stromal cell-derived chemokines that can contribute to the decreasing degrees of quiescence exhibited by primitive normal cells in vivo and in the LTC system (that is, stromal cell-derived factor 1, SDF-1; monocyte chemotactic protein 1, MCP-1; and macrophage inflammatory protein 1 a, MIP-1a [74][75][76] ).…”

Do we have to kill the last CML cell?

“…28 These include decreased intracellular uptake and retention of cytotoxic drugs and tyrosine kinase inhibitors, 28 and resistance to apoptosis. 30,31 Decreased expression of human leukocyte antigen co-stimulatory molecules and targets of adaptive immunity (such as myeloid granule proteins) might also protect stem cells from immune surveillance. 32,33 Many characteristics are shared by leukaemic and normal stem cells, making it difficult to develop a stem cell targeted therapy that is effective against CML and relatively non-toxic.…”

Hematopoietic Stem Cells in Chronic Myeloid Leukemia

“…These stem cells are Ph+, express high levels of CD34 and do not express CD38, CD45RA and CD71, and may spontaneously exit the G 0 phase and enter a state of constant proliferation [122]. Several reports have documented that quiescent cells from CML patients are insensitive to in vitro treatment with Imatinib and Dasatinib [16,123].…”

“…It has been demonstrated that IL-3 and granulocyte-colony G-CSF are produced within primitive CD34+ cells from patients with CML-CP, both of these cytokines stimulate cellular proliferation in an autocrine manner and protect cells from Imatinib-induced apoptosis [122]. …”