The Process of Leukemogenesis

Irons, Richard D.; Stillman, Wayne S.

doi:10.2307/3433169

Cited by 16 publications

(17 citation statements)

References 2 publications

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“…Although the difference in latency between NRAS G12V /Mll-AF9 and Mll-AF9 alone was not statistically significant ( Figure 1B), it is possible that by using more mice, we would detect a statistically significant acceleration of AML. Another possibility 33,34 is that additional mutations may be required to induce oncogenic signaling pathways and/or inhibit tumor suppressing mechanisms despite the presence of NRAS G12V and Mll-AF9. It is also possible that our Vav promoter-tTA-driven TRE-transgene system may not express the level of NRAS G12V expression needed to shorten the latency of AML development in cooperation with Mll-AF9.…”

Section: Discussionmentioning

confidence: 99%

RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia

Kim

Matise

Diers

et al. 2009

Blood

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To study the oncogenic role of the NRAS oncogene (NRAS G12V ) in the context of acute myeloid leukemia (AML), we used a Vav promoter-tetracycline transactivator (Vav-tTA)-driven repressible TRE-NRAS G12V transgene system in Mll-AF9 knock-in mice developing AML. Conditional repression of NRAS G12V expression greatly reduced peripheral white blood cell (WBC) counts in leukemia recipient mice and induced apoptosis in the transplanted AML cells correlated with reduced Ras/Erk signaling. After marked decrease of AML blast cells, myeloproliferative disease (MPD)-like AML relapsed characterized by cells that did not express NRAS G12V . In comparison with primary AML, the MPD-like AML showed significantly reduced aggressiveness, reduced myelosuppression, and a more differentiated phenotype. We conclude that, in AML induced by an Mll-AF9 transgene, NRAS G12V expression contributes to acute leukemia maintenance by suppressing apoptosis and reducing differentiation of leukemia cells. Moreover, NRAS G12V oncogene has a cell nonautonomous role in suppressing erythropoiesis that results in the MPD-like AML show significantly reduced ability to induce anemia. Our results imply that targeting NRAS or RAS oncogene-activated pathways is a good therapeutic strategy for AML and attenuating aggressiveness of relapsed AML. IntroductionKelly and Gilliand have proposed that acute myeloid leukemia (AML) is induced by the cooperation of 2 general classes of mutations. 1 Class I mutations confer cell survival and proliferation advantages and generally result from mutations in genes encoding cell-signaling molecules like NRAS and FLT3. Class II mutations impair differentiation and subsequent apoptosis and, in general, result from mutations in genes encoding transcription factors or chromatin-modifying proteins such as AML1 or mixed lineage leukemia (MLL). Most studies to develop new anticancer drugs have focused on finding efficient inhibitors against the mutant products of class I oncogenes such as ABL, c-KIT, and FLT3. [2][3][4][5][6][7][8] Although previous studies showed that FLT3 inhibition effectively suppresses the cell growth of leukemia induced by the cooperation of an FLT3-activating mutation and an MLL translocation, 9,10 the appropriateness of class I oncogene inhibitors for AML therapy has not been well studied, particularly in leukemia induced in cooperation with a class II oncogene. Conditionally expressed transgenes in mice provide an ideal setting in which to address this issue. Studies have shown that continued expression of oncogenes such as c-Myc or Bcr/Abl is required for maintaining leukemia in transgenic mouse models. [11][12][13] Cancer cells in these models are said to have "oncogene addiction," because they die, differentiate, or become quiescent upon shutting off oncogene expression. 13 To study the functions of a class I mutation in AML, we investigated the role of an NRAS-activating mutation, NRAS G12V , in murine AML induced in combination with the Mll-AF9 oncogene.RAS mutants, which abnormally stimulate RAF/...

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Section: Discussionmentioning

confidence: 99%

RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia

Kim

Matise

Diers

et al. 2009

Blood

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“…In this context, the fact that normal hematopoietic stem cells express AhR-related-inducible metabolizing enzymes such as CYP1A1/1B1 and therefore can generate reactive PAH metabolites when exposed to these environmental chemicals is probably important to consider. Indeed, mutagenic damage to CD34ϩ bone marrow cells is thought to constitute an important initial event in leukemogenesis (Irons and Stillman, 1996), and that PAHs can cause adducts in CD34ϩ cells after their P450-dependent metabolism may thus provide a molecular basis for the potential leukemogenic effects of these chemicals. It is noteworthy that CYP1B1, constitutively present in bone marrow cells, may play a major role in PAH bioactivation as recently suggested (Galvan et al, 2003).…”

Section: Pah Toxicity Toward Human Hematopoietic Stem Cells 697mentioning

confidence: 99%

Human CD34-Positive Hematopoietic Stem Cells Constitute Targets for Carcinogenic Polycyclic Aromatic Hydrocarbons

Grevenynghe

Bernard²,

Langouët³

et al. 2005

J Pharmacol Exp Ther

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Polycyclic aromatic hydrocarbons (PAHs) are major carcinogenic environmental contaminants known to exert bone marrow toxicity and to induce leukemias, suggesting that these chemicals target hematopoietic stem cells. To investigate this hypothesis, we studied the effects of PAHs on cell proliferation and differentiation in human hematopoietic CD34ϩ cell cultures. Benzo(a)pyrene (BP), a prototypical PAH, was shown to markedly impair CD34ϩ cell expansion and to inhibit CD34ϩ cell differentiation into various hematological cell lineages, including erythroid, granulomacrophagic, and megakaryocytic lineages. This was associated with the induction of a caspaseand mitochondrion-related apoptosis process. CD34ϩ progenitor cells were found to exhibit functional expression of the aryl hydrocarbon receptor (AhR), and the use of the pure AhR antagonist 3Ј-methoxy-4Ј-nitroflavone partially counteracted the deleterious effects of BP in CD34ϩ cell cultures, underlining the involvement of AhR in BP toxicity. Additional events such as CYP1A1/1B1-dependent PAH metabolism and adduct formation were also required since 1) 2,3,7,8-tetrachlorodibenzo-pdioxin, a very potent ligand of the AhR that is poorly metabolized and therefore does not generate reactive metabolites in contrast to PAHs, failed to affect CD34ϩ cell expansion; 2) the CYP1A1/1B1 inhibitor ␣-naphthoflavone blocked both BP adduct formation and BP toxicity; and 3) benzo(a)pyrene-trans-7,8-dihydrodiol-9,

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“…Benzene and its metabolites are therefore able to produce chromosome-specific aneuploidy, which most likely plays a role in leukemogenesis. Also in this volume, Irons and Stillman (51,52) argue that clonal cytogenetic abnormalities involving the loss of all or part of chromosomes 5 and 7 are commonly detected in patients who develop myelogenous leukemia after antineoplastic therapy and benzene/solvent exposure. The q arms of chromosomes 5 and 7 are thought to contain key genes, perhaps suppressor genes, involved in myeloid leukemia, and loss of this genetic material could be a critical event.…”

Section: Metabolitesmentioning

confidence: 99%

“…Damage to these proteins would potentially cause DNA strand breakage, mitotic recombination, chromosome translocations, and malsegregation of chromosomes at anaphase to produce aneuploidy. If (51,58) provide further insights into the details of these epigenetic events and propose that recombinational/aneuploidy changes in chromosomes 5 and 7, which produce losses of key genetic material, are important in benzeneinduced leukemia. Our work supports the hypothesis that changes in chromosome 7 play a key role.…”

Section: Role Of Epigenetic Eventsmentioning

confidence: 99%

The Mechanism of Benzene-Induced Leukemia: A Hypothesis and Speculations on the Causes of Leukemia

Smith¹

1996

Environmental Health Perspectives

104

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An overall hypothesis for benzene-induced leukemia is proposed. Key components of the hypothesis include a) activation of benzene in the liver to phenolic metabolites; b) transport of these metabolites to the bone marrow and conversion to semiquinone radicals and quinones via peroxidase enzymes; c) generation of active oxygen species via redox cycling; d) damage to tubulin, histone proteins, topoisomerase 11, other DNA associated proteins, and DNA itself; and e) consequent damage including DNA strand breakage, mitotic recombination, chromosome translocations, and aneuploidy. If these effects take place in stem or early progenitor cells a leukemic clone with selective advantage to grow may arise, as a result of protooncogene activation, gene fusion, and suppressor gene inactivation. Epigenetic effects of benzene metabolites on the bone marrow stroma, and perhaps the stem cell itself, may then foster development and survival of the leukemic clone. Evidence for this hypothesis is mounting with the recent demonstration that benzene induces gene-duplicating mutations in human bone marrow and chromosome-specific aneuploidy and translocations in peripheral blood cells. If this hypothesis is correct, it also potentially implicates phenolic and quinonoid compounds in the induction of "spontaneous" leukemia in man.

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The Process of Leukemogenesis

Cited by 16 publications

References 2 publications

RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia

RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia

Human CD34-Positive Hematopoietic Stem Cells Constitute Targets for Carcinogenic Polycyclic Aromatic Hydrocarbons

The Mechanism of Benzene-Induced Leukemia: A Hypothesis and Speculations on the Causes of Leukemia

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