Leukemic cells infiltrate the ovaries without damaging ovarian reserve in an acute myeloid leukemia mouse model
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ORGANISM(S): Mus musculus (mouse)
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PROVIDER: S-BSST1807 | biostudies-other |
SECONDARY ACCESSION(S): 1
REPOSITORIES: biostudies-other
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Project description:BackgroundCurrent acute myeloid leukemia (AML) therapy fails to eliminate quiescent leukemic blasts in the bone marrow, leading to about 50% of patient relapse by increasing AML burden in the bone marrow, blood, and extramedullar sites. We developed a protein-based nanoparticle conjugated to the potent antimitotic agent Auristatin E that selectively targets AML blasts because of their CXCR4 receptor overexpression (CXCR4+) as compared to normal cells. The therapeutic rationale is based on the involvement of CXCR4 overexpression in leukemic blast homing and quiescence in the bone marrow, and the association of these leukemic stem cells with minimal residual disease, dissemination, chemotherapy resistance, and lower patient survival.MethodsMonomethyl Auristatin E (MMAE) was conjugated with the CXCR4 targeted protein nanoparticle T22-GFP-H6 produced in E. coli. Nanoconjugate internalization and in vitro cell viability assays were performed in CXCR4+ AML cell lines to analyze the specific antineoplastic activity through the CXCR4 receptor. In addition, a disseminated AML animal model was used to evaluate the anticancer effect of T22-GFP-H6-Auristatin in immunosuppressed NSG mice (n = 10/group). U of Mann-Whitney test was used to consider if differences were significant between groups.ResultsT22-GFP-H6-Auristatin was capable to internalize and exert antineoplastic effects through the CXCR4 receptor in THP-1 and SKM-1 CXCR4+ AML cell lines. In addition, repeated administration of the T22-GFP-H6-Auristatin nanoconjugate (9 doses daily) achieves a potent antineoplastic activity by internalizing specifically in the leukemic cells (luminescent THP-1) to selectively eliminate them. This leads to reduced involvement of leukemic cells in the bone marrow, peripheral blood, liver, and spleen, while avoiding toxicity in normal tissues in a luminescent disseminated AML mouse model.ConclusionsA novel nanoconjugate for targeted drug delivery of Auristatin reduces significantly the acute myeloid leukemic cell burden in the bone marrow and blood and blocks its dissemination to extramedullar organs in a CXCR4+ AML model. This selective drug delivery approach validates CXCR4+ AML cells as a target for clinical therapy, not only promising to improve the control of leukemic dissemination but also dramatically reducing the severe toxicity of classical AML therapy.
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Project description:Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines. This was confirmed in vivo using immunodeficient mice engrafted with MOLM-14 cells as well as in a panel of 20 genetically diverse AML patient samples. This effect was dependent on Liver X Receptor β, a major target of DDA. Furthermore, DDA plus idarubicin strongly increased p53BP1 expression and the number of DNA strand breaks in alkaline comet assays as compared to idarubicin alone, whereas DDA alone was non-genotoxic. Mechanistically, DDA induced JNK phosphorylation and the inhibition of AKT phosphorylation, thereby maximizing DNA damage induced by idarubicin and decreasing DNA repair. This activated autophagic cell death machinery in AML cells. Overall, this study shows that the combination of DDA and idarubicin is highly promising and supports clinical trials of dendrogenin A in AML patients.
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Project description:Permanent cure of acute myeloid leukemia (AML) by chemotherapy alone remains elusive for most patients because of the inability to effectively eradicate leukemic stem cells (LSCs), the self-renewing component of the leukemia. To develop therapies that effectively target LSC, one potential strategy is to identify cell surface markers that can distinguish LSC from normal hematopoietic stem cells (HSCs). In this study, we employ a signal sequence trap strategy to isolate cell surface molecules expressed on human AML-LSC and find that CD96, which is a member of the Ig gene superfamily, is a promising candidate as an LSC-specific antigen. FACS analysis demonstrates that CD96 is expressed on the majority of CD34(+)CD38(-) AML cells in many cases (74.0 +/- 25.3% in 19 of 29 cases), whereas only a few (4.9 +/- 1.6%) cells in the normal HSC-enriched population (Lin(-)CD34(+)CD38(-)CD90(+)) expressed CD96 weakly. To examine whether CD96(+) AML cells are enriched for LSC activity, we separated AML cells into CD96(+) and CD96(-) fractions and transplanted them into irradiated newborn Rag2(-/-) gamma(c)(-/-) mice. In four of five samples, only CD96(+) cells showed significant levels of engraftment in bone marrow of the recipient mice. These results demonstrate that CD96 is a cell surface marker present on many AML-LSC and may serve as an LSC-specific therapeutic target.
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Project description:Background/aimsUnderstanding leukemic stem cell (LSC) is important for acute myeloid leukemia (AML) treatment. However, association of LSC with patient prognosis and genetic information in AML patients is unclear.MethodsHere we investigated the associations between genetic information and the various LSC phenotypes, namely multipotent progenitor (MPP)-like, lymphoid primed multipotent progenitor (LMPP)-like and granulocyte-macrophage progenitors (GMP)-like LSC in 52 AML patients.ResultsIn secondary AML patients, MPP-like LSC was significantly higher than de novo AML (p = 0.0037). The proportion of MPP-like LSC was especially high in post-myeloproliferative neoplasm AML (p = 0.0485). There was no correlation between age and LSC phenotype. Mutations of KRAS and NRAS were observed in MPP-like LSC dominant patients, TP53 and ASXL1 mutations in LMPP-like LSC dominant patients, and CEBPA, DNMT3A and IDH1 mutations in GMP-like LSC dominant patients. Furthermore, KRAS mutation was significantly associated with MPP-like LSC expression (p = 0.0540), and TP53 mutation with LMPP-like LSC expression (p = 0.0276). When the patients were separated according to the combined risk including next generation sequencing data, the poorer the prognosis, the higher the LMPP-like LSC expression (p = 0.0052). This suggests that the dominant phenotype of LSC is one of the important factors in predicting the prognosis and treatment of AML.ConclusionLSC phenotype in AML is closely associated with the recurrent mutations which has prognostic implication. Further research to confirm the meaning of LSC phenotype in the context of genetic aberration is warranted.
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Project description:Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia (AML), and thus represents a potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD+-dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity in different tumor cells. Here, we demonstrate that also CD34+ blasts from AML patients show ongoing DNA damage and SIRT6 overexpression. Indeed, we identified a poor-prognostic subset of patients, with widespread instability, which relies on SIRT6 to compensate for DNA-replication stress. As a result, SIRT6 depletion compromises the ability of leukemia cells to repair DNA double-strand breaks that, in turn, increases their sensitivity to daunorubicin and Ara-C, both in vitro and in vivo In contrast, low SIRT6 levels observed in normal CD34+ hematopoietic progenitors explain their weaker sensitivity to genotoxic stress. Intriguingly, we have identified DNA-PKcs and CtIP deacetylation as crucial for SIRT6-mediated DNA repair. Together, our data suggest that inactivation of SIRT6 in leukemia cells leads to disruption of DNA-repair mechanisms, genomic instability and aggressive AML. This synthetic lethal approach, enhancing DNA damage while concomitantly blocking repair responses, provides the rationale for the clinical evaluation of SIRT6 modulators in the treatment of leukemia.
| S-EPMC5777193 | biostudies-literature
Project description:IntroductionTreatment failure in acute myeloid leukemia is probably caused by the presence of leukemia initiating cells, also referred to as leukemic stem cells, at diagnosis and their persistence after therapy. Specific identification of leukemia stem cells and their discrimination from normal hematopoietic stem cells would greatly contribute to risk stratification and could predict possible relapses.ResultsFor identification of leukemic stem cells, we developed flow cytometric methods using leukemic stem cell associated markers and newly-defined (light scatter) aberrancies. The nature of the putative leukemic stem cells and normal hematopoietic stem cells, present in the same patient's bone marrow, was demonstrated in eight patients by the presence or absence of molecular aberrancies and/or leukemic engraftment in NOD-SCID IL-2R?-/- mice. At diagnosis (n=88), the frequency of the thus defined neoplastic part of CD34+CD38- putative stem cell compartment had a strong prognostic impact, while the neoplastic parts of the CD34+CD38+ and CD34- putative stem cell compartments had no prognostic impact at all. After different courses of therapy, higher percentages of neoplastic CD34+CD38- cells in complete remission strongly correlated with shorter patient survival (n=91). Moreover, combining neoplastic CD34+CD38- frequencies with frequencies of minimal residual disease cells (n=91), which reflect the total neoplastic burden, revealed four patient groups with different survival.Conclusion and perspectiveDiscrimination between putative leukemia stem cells and normal hematopoietic stem cells in this large-scale study allowed to demonstrate the clinical importance of putative CD34+CD38- leukemia stem cells in AML. Moreover, it offers new opportunities for the development of therapies directed against leukemia stem cells, that would spare normal hematopoietic stem cells, and, moreover, enables in vivo and ex vivo screening for potential efficacy and toxicity of new therapies.
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