Chronic Myelogenous Leukemia â?? Identifying the Hydra’s Heads
Michael F. Clarke, M.D.
Chronic myelogenous leukemia (CML) begins as an indolent disease in which the myeloid lineages in the bone marrow and blood gradually expand. Untreated, this chronic phase of CML inexorably progresses to an accelerated phase and finally to a blast crisis, in which large numbers of blast cells appear in the bone marrow and blood. The hallmark of CML is the Philadelphia chromosome, which corresponds to a t(9;22) translocation in which sequences of BCR that encode the N-terminal region of the BCR protein fuse with the tyrosine kinase catalytic domain of the ABL oncogene. This chimeric gene (BCR-ABL) is central
PU.1 is a suppressor of myeloid leukemia, inactivated in mice by gene deletion and mutation of its DNA-binding domain.
In most myeloid leukemias induced in mice by gamma-radiation, one copy of chromosome 2 has suffered a deletion. To search for a potential tumor suppressor gene in that region, we have delineated the deletions in a panel of these tumors. A commonly deleted region of 2 Mbp includes the gene encoding the PU.1 transcription factor, a powerful inducer of granulocytic/monocytic differentiation. Significantly, in 87% of these tumors the remaining PU.1 allele exhibited point mutations in the PU.1 DNA-binding domain. Surprisingly, 86% of these mutations altered a single CpG, implicating deamination of deoxycytidine, a common mutational mechanism, as the origin of this lesion. The hot spot resides in the codon for a contact residue essential for DNA-binding by PU.1. In keeping with a tumor suppressor role for PU.1, enforced expression of wild-type PU.1 in the pro-myelocytic leukemia cells inhibited their clonogenic growth, induced monocytic differentiation and elicited apoptosis. The mutant PU.1 found in tumors retained only minimal growth suppressive function. The results suggest that PU.1 normally suppresses development of myeloid leukemia by promoting differentiation, and that the combination of gene deletion and a point mutation that impairs its ability to bind DNA is particularly leukemogenic.
Trisomy 8 in Philadelphia-negative cells during imatinib therapy.
Targeted therapy with imatinib selectively suppresses Philadelphia-positive cells in chronic myeloid leukemia cells, with reappearance of apparently normal hemopoiesis in a considerable number of patients. Recently, clonal abnormalities have been observed in Philadelphia-negative cells during imatinib therapy, the biologic and prognostic significance of which is actually unknown. A case of trisomy 8 occurring in Philadelphia-negative cells, which was treated by bone marrow transplantation, is reported. Chromosomal abnormalities in Philadelphia-negative cells do not seem to herald disease transformation, but the long-term prognosis may be influenced by an increased incidence of myelodysplasia in younger patients. Am. J. Hematol. 77:88-89, 2004. Copyright 2004 Wiley-Liss, Inc.
US canoers practice in the waters of the Schinias Rowing and Canoeing Centre outside Athens. (AFP/Mladen Antonov)
Depression, cigarette smoking, and hematopoietic stem cell transplantation outcome.
BACKGROUND: The relationships between psychological and behavioral variables and patient outcomes after hematopoietic stem cell transplantation (HSCT) are not known definitively but have great potential importance, since this lifesaving procedure is used increasingly to treat a variety of malignancies. The objective of this study was to evaluate psychosocial predictors of long-term survival and disease recurrence after patients underwent allogeneic HSCT for chronic myelogenous leukemia (CML). METHODS: In this prospective cohort study, 114 adults were admitted for allogeneic HSCT to the Brigham and Women’s Hospital between July, 1997 and January, 2002. The median follow-up was 882 days, and serial measures were taken for mood and substance use 6 months and 12 months posttransplantation. RESULTS: With a 93% participation rate by all potentially eligible patients and with < 3% of patients loss to follow-up, univariate predictors of long-term survival and recurrence were identified. Cox proportional hazards regression models for survival and recurrence were developed. Depressive symptoms, as measured by the most recent Beck Depression Inventory (BDI), increased the risk of death by 7% for each point increase in the BDI score (P = 0.006). Fourteen of 17 patients who developed recurrent disease were cigarette smokers with an average of 22.3 pack-years. For each pack-year of cigarette smoking, the risk of recurrence increased by 1.7% (P = 0.01). CONCLUSIONS: This study assessed the role of psychosocial variables prospectively among a clinically homogeneous but representative cohort of patients who underwent allogeneic HSCT. Although additional confirmatory studies are pending, it appears that depressive symptoms posttransplantation and cigarette smoking prior to transplantation affect outcomes adversely and may represent opportunities to improve the morbidity and mortality associated with HSCT for patients with CML.
Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970.
Oncogenic mutations of the receptor tyrosine kinase KIT occur in gastrointestinal stromal tumors (GIST), some cases of acute myelogenous leukemia (AML) and systemic mastocytosis (SM). GISTs commonly contain mutations of the KIT juxtamembrane region while SM and AML harbor active site KIT mutations. Imatinib, which potently inhibits juxtamembrane mutants, is effective for the treatment of GISTs but has no activity against active site mutants. We analyzed the inhibitory potential of two small molecule inhibitors, MLN518 and PD180970 against different classes of KIT mutants. Both compounds inhibit the growth of cell lines expressing juxtamembrane mutant KIT. MLN518 additionally targets active site mutant cell lines, inhibiting cell proliferation, KIT and Stat3 phosphorylation and inducing apoptosis at concentrations that may be clinically achievable. As phase I clinical trials of MLN518 in AML have shown little toxicity, our data suggest MLN518 is a promising candidate for the treatment of SM or AML with KIT mutations.
Sesquiterpene aminoquinones, from a marine sponge, induce erythroid differentiation in human chronic myelogenous leukemia, k562 cells.
A new sesquiterpene aminoquinone, 5-epi-smenospongorine, together with nine known sesquiterpene quinone/phenols, was isolated as differentiation-inducing substances to K562 cells into erythroblast from the marine sponge Dactylospongia elegans. The structure-activity relationship study of these compounds clarified that the quinone skeleton is indispensable and the amino group plays an important role for their differentiation-inducing activity to K562 cells into erythroblast.
Erythropoietin overcomes imatinib-induced apoptosis and induces erythroid differentiation in TF-1/bcr-abl cells.
Targeting BCR-ABL tyrosine kinase by treatment with the selective inhibitor imatinib (formerly STI571, Gleevec) has proved to be highly efficient for inhibiting leukemic growth in vitro. In addition, in clinical trials, imatinib has produced high response rates in patients with chronic myeloid leukemia (CML) in chronic phase and blastic crisis. However, episodes of severe cytopenia were also frequently observed, leading to discontinuation of therapy in some cases. Therefore, it is important to examine whether administration of cytokines overcomes the adverse effects of imatinib in in vitro systems. In this study, we examine the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) on TF-1/bcr-abl (which was generated by transduction of a bcr-abl fusion gene into the TF-1 cell line) as a model system for CML with blastic crisis. Imatinib induced apoptosis in TF-1/bcr-abl cells but not in the parental TF-1 cells. However, GM-CSF, a survival factor of the parental TF-1 cells, protected TF-1/bcr-abl cells from imatinib-induced apoptosis in a dose-dependent manner. Concomitantly, constitutive phosphorylation of Stat5 and FKHRL1 was significantly inhibited by imatinib, and the inhibition was canceled by the addition of GM-CSF, accompanied by upregulation of Bcl-xL and downregulation of p27/Kip1. In addition, although untreated TF-1/bcr-abl cells had lost responsiveness to both GM-CSF and EPO and showed autonomous growth, GM-CSF enhanced phosphorylation of Stat5 and FKHRL1 in these cells. Importantly, imatinib-treated TF-1/bcr-abl cells differentiated into hemoglobin-positive cells in the presence of EPO, as in the case for the parental TF-1 cells. Taken together, imatinib-treated CML cells may differentiate into mature cells in the presence of differentiation-inducing cytokines such as EPO.