Discovering early molecular determinants of leukemogenesis.

Department of Medicine and Molecular and Medical Genetics, Oregon Health and Sciences University, Oregon, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 04/2008; 118(3):847-50. DOI: 10.1172/JCI35109
Source: PubMed


Truncating mutations of the G-CSF receptor are found during disease course in nearly half of all patients with severe congenital neutropenia. In this issue of the JCI, Liu et al. demonstrate that these mutations confer a competitive clonal advantage upon HSCs in mice and that the advantage is conditional because it is observed only in the presence of the ligand G-CSF (see the related article beginning on page 946). Once activated, the mutant receptor requires the function of Stat5 in order to effect clonal expansion of this stem cell population. The results support the notion that early molecular steps in this and other neoplastic processes represent adaptations in which, through somatic mutations, "unfit" stem cells gain a measure of fitness by altering their relationships with their microenvironment.

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    • "We still do not understand the relationship of defective DNA repair to progressive bone marrow failure, even though we know that this phenotype arises from impaired selfrenewal of hematopoietic stem cells (Carreau et al., 1999). Additional defects not easily understood from defects in DNA repair, include poor resistance to oxidative damage, interaction with inflammation pathways, and hyperactivation of the MAPK pathway leading to overproduction of TNF-a (Bagby, 2008; Briot et al., 2008; Li et al., 2007; Sejas et al., 2007; Uziel et al., 2008). At least some of these difficult to explain phenotypes may involve key functions of FANCs distinct from the NC complex. "
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    ABSTRACT: Fanconi anemia (FA) is a human disease of bone marrow failure, leukemia, squamous cell carcinoma, and developmental anomalies, including hypogonadism and infertility. Bone marrow transplants improve hematopoietic phenotypes but do not prevent other cancers. FA arises from mutation in any of the 15 FANC genes that cooperate to repair double stranded DNA breaks by homologous recombination. Zebrafish has a single ortholog of each human FANC gene and unexpectedly, mutations in at least two of them (fancl and fancd1(brca2)) lead to female-to-male sex reversal. Investigations show that, as in human, zebrafish fanc genes are required for genome stability and for suppressing apoptosis in tissue culture cells, in embryos treated with DNA damaging agents, and in meiotic germ cells. The sex reversal phenotype requires the action of Tp53 (p53), an activator of apoptosis. These results suggest that in normal sex determination, zebrafish oocytes passing through meiosis signal the gonadal soma to maintain expression of aromatase, an enzyme that converts androgen to estrogen, thereby feminizing the gonad and the individual. According to this model, normal male and female zebrafish differ in genetic factors that control the strength of the late meiotic oocyte-derived signal, probably by regulating the number of meiotic oocytes, which environmental factors can also alter. Transcripts from fancd1(brca2) localize at the animal pole of the zebrafish oocyte cytoplasm and are required for normal oocyte nuclear architecture, for normal embryonic development, and for preventing ovarian tumors. Embryonic DNA repair and sex reversal phenotypes provide assays for the screening of small molecule libraries for therapeutic substances for FA.
    Methods in cell biology 01/2011; 105:461-90. DOI:10.1016/B978-0-12-381320-6.00020-5 · 1.42 Impact Factor
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    • "Recently we found that G-CSF-treated myeloid progenitor cells from CN patients expressed high levels of activated phospho-STAT5 protein (Skokowa et al, 2007; Germeshausen et al, 2008b). This data was further confirmed by findings in a recently published mouse model (Liu et al, 2008) demonstrating that CSF3R mutations confer a strong clonal advantage of hematopoietic stem cells via activation of STAT5 that is depending on exogenous G-CSF (Liu et al, 2008; Bagby 2008). Therefore, one possible mechanism of leukemogenesis could be the prolonged activation of STAT5 in CSF3R mutation-bearing cells rendering them to additional molecular aberrations. "
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    ABSTRACT: Congenital Neutropenia (CN) is a heterogeneous bone marrow failure syndrome characterized by a maturation arrest of myelopoiesis at the level of the promyelocyte/myelocyte stage with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l. There are two major subtypes of CN as judged by inheritance: an autosomal dominant subtype, e.g. defined by neutrophil elastase mutations (approximately 60% of patients) and an autosomal recessive subtype (approximately 30% of patients), both presenting with the same clinical and morphological phenotype. Different mutations have been described (e.g. HAX1, p14 etc) in autosomal recessive CN, with HAX1 mutations in the majority of these patients. CN in common is considered as a preleukemic syndrome, since the cumulative incidence for leukemia is more than 25% after 20 years of observation. Leukemias occur in both, the autosomal dominant and recessive subtypes of CN. The individual risk for each genetic subtype needs to be further evaluated. Numbers of patients tested for the underlying genetic defect are still limited. Acquired G-CSFR (CSF3R) mutations are detected in approximately 80% of CN patients who developed acute myeloid leukemia independent of the ELA2 or HAX1 genetic subtype, suggesting that these mutations are involved in leukemogenesis. As the majority of patients benefit from G-CSF administration, HSCT should be restricted to non-responders and patients with leukaemic transformation.
    British Journal of Haematology 02/2009; 144(4):459-67. DOI:10.1111/j.1365-2141.2008.07425.x · 4.71 Impact Factor
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    ABSTRACT: Although it has recently been thought that a number of medicinal plants and foodstuffs have antitumor and antimetastatic activities, the basis for this hearsay is unclear. Therefore, to clarify whether natural products have antitumor and antimtastatic actions, I have been using biochemical and pharmacological approaches to study the natural products isolated from various medicinal plants and foodstuffs. In the review, we will introduce the biological and pharmacological actions of various components isolated from some medicinal plants and foodstuffs on tumor growth and metastasis in tumor-bearing mice. Chitosan and fish oils prevented the adverse reactions such as gastrointestinal toxicity and myelotoxicity caused by cancer chemotherapy drugs without interfering the antitumor activity of chemotherapy drugs. Stilbenes derivatives isolated from Cassia or Polygonum species inhibited the tumor growth and metastasis to the lung in highly metastaic tumor-bearing mice. Furthermore, I found that stilbenes inhibited the angiogenesis in in vivo and in vitro models.
    Studies in Natural Products Chemistry 01/2003; 28:559-586. DOI:10.1016/S1572-5995(03)80149-7
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