Chronic myelocytic leukemia (CML): failure to detect residual normal committed stem cells in vitro

Singer, Jack W.; Fialkow, Philip J.; Steinmann, Laura; Najfeld, Vesna; Stein, S. J.; Robinson, William A.

doi:10.1182/blood.v53.2.264.264

Cited by 50 publications

(3 citation statements)

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“…By the time of diagnosis, increased numbers of malignant precursors are detected among all haematopoietic lineages typically in association with a marked increase of both mature neutrophils and platelets, but not red cells (Faderl et al , 1999). In addition, it has been reported that an increased proliferation due to deregulation of CD34 + CML haematopoietic progenitor cells (HPC) could be responsible for both the pronounced expansion of leukaemic progenitors (Shtivelman et al , 1985; Eaves et al , 1986; Daley et al , 1990; Heisterkamp et al , 1990) and the excessive production of leukaemia‐colony forming units (CFU‐L) found in CML patients (Singer et al , 1979; Eaves et al , 1998). In turn, a decreased rate of apoptosis has also been reported to lead to the selective expansion of the BCR / ABL haematopoietic cell compartments in CML (Bedi et al , 1994; McGahon et al , 1994; Smetsers et al , 1994; Rowley et al , 1996).…”

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Impact of BCR/ABL gene expression on the proliferative rate of different subpopulations of haematopoietic cells in chronic myeloid leukaemia

et al. 2006

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SummaryDespite the effects of BCR/ABL on cell proliferation, no study has compared the proliferative rate of different haematopoietic cell compartments from chronic myeloid leukaemia (CML) with those of normal bone marrow (NBM). We comparatively analysed the cell cycle distribution and BCR/ABL expression in different compartments of BM cells from 15 CML and 11 NBM. Overall, our results showed similar proliferative indices in CML patients and NBM. However, CD34 + myeloid precursors from CML patients displayed an increased proportion of S + G 2 /M-phase cells (P ¼ 0AE04), while no significant differences were found between CML and NBM for other BM cell subsets analysed. In BM cells separated by fluorescence-activated cell sorting, decreasing levels of BCR/ABL mRNA were found from CD34 + / CD38 + myeloid precursors to myeloblasts; BCR/ABL expression increased afterwards with a peak at the myelocyte/metamyelocyte stage, decreasing in the more mature band/neutrophil compartment. Unexpectedly, BCR/ABL gene expression showed an inverse correlation with the proportion of S + G 2 /M-phase cells (R ¼ )0AE33; P ¼ 0AE04). These results suggest that in CML, BCR/ABL expression is associated with an increased proliferation of CD34 + myeloid haematopoietic progenitor cells but not of other more mature myeloid precursors, as confirmed by the observation of an inverse correlation between the amount of BCR/ABL transcripts and the proportion of S + G 2 /M-phase cells.

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confidence: 99%

Impact of BCR/ABL gene expression on the proliferative rate of different subpopulations of haematopoietic cells in chronic myeloid leukaemia

et al. 2006

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“…Genetic studies performed over 20 years ago demonstrated that the malignant clone in CML is a pluripotent hematopoietic stem cell, capable of differentiating into myeloid cells, monocytes, erythrocytes, and platelets (Bernstein et al, 1992;Douer et al, 1981;Fialkow et al, 1977;Koeffler et al, 1980;Martin et al, 1980;Singer et al, 1980;Singer et al, 1979). These studies identified that only single enzyme phenotypes of the X-linked G6PD isoenzyme were present in cells across the spectrum of hematopoietic lineages in women with CML who were heterozygous for this gene.…”

Section: Lessons From CML a Disorder Of The Hematopoietic Stem Cellmentioning

confidence: 99%

Immunologic targeting of the cancer stem cell

2008

StemBook

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Growing evidence has suggested that lack of eradication of the malignant stem cell forms the basis for cancer relapse and progression. In this regard, the clinical experiences of treating chronic myelogenous leukemia (CML), a prototypical stem cell disease, have been instructive, and are illustrative of the challenges facing the treatment of cancer when using potent cytoreductive agents that incompletely eradicate minimal residual disease. On the other hand, several decades of clinical and laboratory experience have demonstrated the curative potential of allogeneic stem cell transplantation for CML and other hematologic malignancies. As reviewed in this chapter, these studies have clearly demonstrated the curative potential of immune-based recognition of tumor cells, including the malignant progenitor cell population. These data set the stage for newer approaches that focus on immune targeting of antigens that are present on the cancer stem cell. Rational immune targeting

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“…Although differentiation per se does not appear to be perturbed in the chronic phase of CML, the neoplastic (Ph + / BCR‐ABL + ) clone has usually already become dominant by the time of diagnosis. In addition, by this time, >95% of all of the intermediate myeloid progenitors detectable by conventional in vitro colony‐forming cell (CFC) assays are leukemic 2,3. Because these progenitors can continue to differentiate normally, they go on to produce all of the blood cells generated in patients with chronic phase disease with the exception of some of the lymphoid elements 4.…”

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confidence: 99%

New Models to Investigate Mechanisms of Disease Genesis from Primitive BCR‐ABL⁺ Hematopoietic Cells

Eaves

Jiang

Eisterer

et al. 2003

Annals of the New York Academy of Sciences

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Three years ago we described a novel autocrine IL-3/G-CSF mechanism active in the leukemic CD34(+) cells from chronic myeloid leukemia (CML) patients in chronic phase (PNAS 96: 12804-12809, [1999]). We also showed that exposure of the most primitive CD34(+) cells from normal human bone marrow to excess IL-3 stimulates not only the division of these cells but also their differentiation. In contrast, both IL-3 and G-CSF cause an expansion of the more mature types of normal CD34(+) progenitors. These findings suggested that the autocrine IL-3/G-CSF mechanism active in CML stem cells can compromise their self-renewal in spite of increasing their proliferative activity, which, in turn, might explain the paradoxically slow rate of expansion of this compartment over time in patients with latent disease. To investigate this hypothesis, we have begun to characterize the numbers and types of cells generated from chronic phase CML patients' cells transplanted into adult immunodeficient mice or fetal sheep, and also from transplants of primitive murine and human hematopoietic cells transduced with a retroviral BCR-ABL vector. Our findings to date using these models reinforce the importance of the autocrine IL-3/G-CSF mechanism in the development of CML. BCR-ABL appears to directly activate IL-3 and G-CSF production in primitive hematopoietic cells and this is important to their transplantable leukemogenic activity. However, the development in vivo of an overt leukemia from primitive BCR-ABL(+) hematopoietic cells can be very delayed. These models thus offer new opportunities for analyzing the molecular events that underlie the pathogenesis of human CML and the future testing of new therapeutic approaches.

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Chronic myelocytic leukemia (CML): failure to detect residual normal committed stem cells in vitro

Cited by 50 publications

References 9 publications

Impact of BCR/ABL gene expression on the proliferative rate of different subpopulations of haematopoietic cells in chronic myeloid leukaemia

Impact of BCR/ABL gene expression on the proliferative rate of different subpopulations of haematopoietic cells in chronic myeloid leukaemia

Immunologic targeting of the cancer stem cell

New Models to Investigate Mechanisms of Disease Genesis from Primitive BCR‐ABL⁺ Hematopoietic Cells

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Chronic myelocytic leukemia (CML): failure to detect residual normal committed stem cells in vitro

Cited by 50 publications

References 9 publications

Impact of BCR/ABL gene expression on the proliferative rate of different subpopulations of haematopoietic cells in chronic myeloid leukaemia

Impact of BCR/ABL gene expression on the proliferative rate of different subpopulations of haematopoietic cells in chronic myeloid leukaemia

Immunologic targeting of the cancer stem cell

New Models to Investigate Mechanisms of Disease Genesis from Primitive BCR‐ABL+ Hematopoietic Cells

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Product

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New Models to Investigate Mechanisms of Disease Genesis from Primitive BCR‐ABL⁺ Hematopoietic Cells