Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML.

  title={Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML.},
  author={Catriona H. M. Jamieson and Laurie E. Ailles and Scott J. Dylla and Manja Muijtjens and Carol D. Jones and James L. Zehnder and Jason Gotlib and Kevin Li and Markus G. Manz and Armand Keating and Charles L. Sawyers and Irving L. Weissman},
  journal={The New England journal of medicine},
  volume={351 7},
BACKGROUND The progression of chronic myelogenous leukemia (CML) to blast crisis is supported by self-renewing leukemic stem cells. In normal mouse hematopoietic stem cells, the process of self-renewal involves the beta-catenin-signaling pathway. We investigated whether leukemic stem cells in CML also use the beta-catenin pathway for self-renewal. METHODS We used fluorescence-activated cell sorting to isolate hematopoietic stem cells, common myeloid progenitors, granulocyte-macrophage… 

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The chronic myeloid leukemia stem cell.

Characterization of CML stem cells has demonstrated that a small percentage of these cells are quiescent despite culture with growth factors, suggesting drug insensitivity leads to disease persistence that may lead to disease relapse even despite an initial response to imatinib.

BCR-ABL-transformed GMP as myeloid leukemic stem cells

Results provide further evidence that BCR-ABL-transformed GMP with abnormal β-catenin activity can function as leukemic stem cells.

WNT/β-Catenin Signaling in Leukemia

Interestingly, individual components of the WNT/β-catenin signaling pathway have a lineage-specific role and regulate stem cell self-renewal, proliferation, or differentiation specifically in one leukemia ­subset.

Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia.

It is shown that retroviral expression of Hes1 immortalizes common myeloid progenitors and granulocyte-macrophage progensitors in the presence of interleukin-3, conferring permanent replating capability on these cells.

Bmi 1 reprograms CML B-lymphoid progenitors to become BALL – initiating cells

It is reported that Bmi1 transforms and reprograms CML B-lymphoid progenitors into stem cell leukemia (Scl) promoter-driven, self-renewing, leukemiainitiating cells to result in B-allymphoid leukemia (B-ALL) in vivo.

Bmi1 reprograms CML B-lymphoid progenitors to become B-ALL-initiating cells.

It is reported that Bmi1 transforms and reprograms CML B-lymphoid progenitors into stem cell leukemia (Scl) promoter-driven, self-renewing, leukemia-initiating cells to result in B-allymphoid leukemia (B-ALL) in vivo.

C/EBPβ promotes BCR–ABL-mediated myeloid expansion and leukemic stem cell exhaustion

Results suggest that C/EBPβ is involved in BCR–ABL-mediated myeloid expansion and further elucidation of the molecular mechanisms underlying the C/ EBPβ-mediated stem cell loss might reveal a novel therapeutic strategy for eradication of CML stem cells.

CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression.

The results reveal a mechanism by which adaptive immunity contributes to leukemia progression, and targeting CD27 on LSCs may represent an attractive therapeutic approach to blocking the Wnt/β-catenin pathway in CML.

Instability of BCR-ABL gene in primary and cultured chronic myeloid leukemia stem cells.

Primary CML stem cells display instability of the BCR-ABL fusion gene both in vivo and in vitro, suggesting that patients may possess leukemic stem cells with BCR -ABL kinase mutations before initiation of BCR,ABL-targeted therapies and would likely be predisposed to develop resistance to these agents.

to Maintain Cell Survival Granulocyte/Macrophage Progenitor Stages Hematopoietic Stem Cell and the Human Flt3 Is Expressed at the

It is found that human Flt3 signaling prevents stem and progenitors from spontaneous apoptotic cell death at least through up-regulating Mcl-1, an indispensable survival factor for hematopoiesis.



Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro.

In vitro insensitivity to STI571, in combination with its demonstrated antiproliferative activity, could translate into disease relapse after prolonged therapy despite dramatic short-term responses in vivo.

Regulated expression of P210 Bcr-Abl during embryonic stem cell differentiation stimulates multipotential progenitor expansion and myeloid cell fate.

  • T. EraO. Witte
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2000
Findings are consistent with Bcr-Abl being the sole genetic change needed for the establishment of the chronic phase of CML and provide a powerful system for the analysis of any genetic change that alters cell growth and lineage choices of the hematopoietic stem cell.

Prospective isolation of human clonogenic common myeloid progenitors

The prospective isolation of early developmental intermediates, the human clonogenic common myeloid progenitors and their downstream progeny, the granulocyte/macrophage and megakaryocyte/erythrocyte progenitor populations are shown.

Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling

It is demonstrated that constitutive Notch1 signaling in hematopoietic cells established immortalized, cytokine-dependent cell lines that generated progeny with either lymphoid or myeloid characteristics both in vitro and in vivo.

Normal and leukemic SCID-repopulating cells (SRC) coexist in the bone marrow and peripheral blood from CML patients in chronic phase, whereas leukemic SRC are detected in blast crisis.

It is shown that irradiated severe combined immunodeficient mice can be transplanted with both normal and neoplastic cells from CML patients with either chronic or blast phase disease, and the feasibility of using this model for the future characterization of transplantable CML stem cells during disease progression is established.

AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation.

The data strongly suggest that the acquisition of the t(8;21) occurs at the level of stem cells capable of differentiating into B cells as well as all myeloid lineages, and that a fraction of the AML1/ETO-expressing stem cells undergo additional oncogenic event(s) that ultimately leads to transformation into AML.

Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias

Data indicate that a MPD can arise in mice without expression of BCR/ABL in HSCs and that additional mutations inhibiting programmed cell death may be critical in the transition of this disease to blast-crisis leukemia.

Inducible expression of BCR/ABL using human CD34 regulatory elements results in a megakaryocytic myeloproliferative syndrome.

A new model of an inducible BCR/ABL disease by directing the expression of the oncogene to megakaryocytic progenitor cells within the murine bone marrow using the tetracycline-responsive expression system under the control of human CD34 regulatory elements is described.

Efficient transplantation of BCR-ABL-induced chronic myelogenous leukemia-like syndrome in mice.

The inability to transplant the disease from mice developing the early-onset CML-like syndrome suggests that this disorder may originate from more differentiated progenitor cells with limited replication capacity that have undergone clonal expansion but are not immortalized.

Isolation of a candidate human hematopoietic stem-cell population.

By extrapolation, the rare human Thy-1+Lin-CD34+ cell population contains pluripotent hematopoietic progenitors; it is proposed that it is highly enriched for candidate hematopolietic stem cells.