Abstract: |
The chronological history of the important discoveries leading to our present understanding of the essential clinical, biological, biochemical, and molecular features of chronic myelogenous leukemia (CML) are first reviewed, focusing in particular on abnormalities that are responsible for the massive myeloid expansion. CML is an excellent target for the development of selective treatment because of its highly consistent genetic abnormality and qualitatively different fusion gene product, p210bcr-abl. It is likely that the multiple signaling pathways dysregulated by p210bcr-abl are sufficient to explain all the initial manifestations of the chronic phase of the disease, although understanding of the circuitry is still very incomplete. Evidence is presented that the signaling pathways that are constitutively activated in CML stem cells and primitive progenitors cooperate with cytokines to increase the proportion of stem cells that are activated and thereby increase recruitment into the committed progenitor cell pool, and that this increased activation is probably the primary cause of the massive myeloid expansion in CML. The cooperative interactions between Bcr-Abl and cytokine-activated pathways interfere with the synergistic interactions between multiple cytokines that are normally required for the activation of stem cells, while at the same time causing numerous subtle biochemical and functional abnormalities in the later progenitors and precursor cells. The committed CML progenitors have discordant maturation and reduced proliferative capacity compared to normal committed progenitors, and like them, are destined to die after a limited number of divisions. Thus, the primary goal of any curative strategy must be to eliminate all Philadelphia positive (Ph+) primitive cells that are capable of symmetric division and thereby able to expand the Ph+ stem cell pool and recreate the disease. Several highly potent and moderately selective inhibitors of Bcr-Abl kinase have recently been discovered that are capable of killing the majority of actively proliferating early CML progenitors with minimal effects on normal progenitors. However, like their normal counterparts, most of the CML primitive stem cells are quiescent at any given time and are relatively invulnerable to the Bcr-Abl kinase inhibitors as well as other drugs. We propose that survival of dormant Ph+ stem cells may be the most important reason for the inability to cure the disease during initial treatment, while resistance to the inhibitors and other drugs becomes increasingly important later. An outline of a possible curative strategy is presented that attempts to take advantage of the subtle differences in the proliferative behavior of normal and Ph+ stem cells and the newly discovered selective inhibitors of Bcr-Abl. |
Keywords: |
signal transduction; treatment outcome; unclassified drug; busulfan; hydroxyurea; clinical feature; clinical trial; review; cytotoxic agent; diarrhea; drug potentiation; nonhuman; antineoplastic agents; alpha interferon; paclitaxel; cytarabine; antineoplastic agent; cell proliferation; cell death; cell division; cell function; imatinib; stem cell factor; unindexed drug; cell maturation; protein kinase inhibitor; protein protein interaction; nausea; vomiting; granulocyte macrophage colony stimulating factor; gene product; cyclophosphamide; drug potency; 6 (2,6 dichlorophenyl) 2 [3 (hydroxymethyl)anilino] 8 methylpyrido[2,3 d]pyrimidin 7(8h) one; chronic myeloid leukemia; drug selectivity; rash; arsenic trioxide; cytokine; whole body radiation; regulatory mechanism; early cancer; leukemogenesis; gene fusion; graft versus host reaction; hematopoietic stem cells; cell count; hematopoietic stem cell; bcr abl protein; genetic disorder; anthracycline derivative; pyrimidine derivative; ic 50; bone marrow transplantation; cell activation; granulocyte colony stimulating factor; protein kinase; retinoic acid; fusion proteins, bcr-abl; concentration response; fluid retention; chronic myelogenous leukemia; muscle cramp; philadelphia 1 chromosome; qualitative analysis; 6 (2,6 dichlorophenyl) 2 (4 fluoro 3 methylanilino) 8 methyl 8h pyrido[2,3 d]pyrimidin 7 one; 6 (2,6 dichlorophenyl) 8 methyl 2 (3 methylthioanilino) 8h pyrido[2,3 d]pyrimidin 7 one; ribozyme; antisense oligonucleotide; hexamethylenebisacetamide; leukemia, myeloid, chronic; vitamin d derivative; humans; human; priority journal; curative strategies; bryostatin
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