Eradicating acute myeloid leukemia in a MllPTD/wt:Flt3ITD/wt murine model: a path to novel therapeutic approaches for human disease

Bernot, Kelsie M.; Nemer, John S.; Santhanam, Ramasamy; Liu, Shujun; Zorko, Nicholas; Whitman, Susan P.; Dickerson, Kathryn E.; Zhang, Mengzi; Xiao, Yang; McConnell, Kathleen; Ahmed, Elshafa H.; Muñoz, Maura R.; Siebenaler, Ronald F.; Marcucci, Gabriel G.; Mundy-Bosse, Bethany L.; Brook, Daniel; Garman, Sabrina; Dorrance, Adrienne M.; Zhang, Xiaoli; Zhang, Jianying; Lee, Robert J.; Blum, William; Caligiuri, Michael A.; Marcucci, Guido

doi:10.1182/blood-2013-06-507426

Cited by 31 publications

(28 citation statements)

References 28 publications

(45 reference statements)

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“…AML blasts transfected with miR-29b also showed significant decreases in SPARC levels at 24 hours ( Figure 8C). We have previously shown that miR-29b is downregulated in AML via a SP1/NF-κB/HDAC inhibitory complex and that pharmacologic disruption of this complex results in miR-29b upregulation and downregulation of direct (i.e., SP1, DNMT3A, DNMT3B) and indirect (i.e., DNMT1, FLT3, KIT) miR-29b targets (45,48,49). Consistent with these reports, we showed that bortezomib at concentrations achievable in vivo (45,50) significantly increased miR29b expression ( Figure 8D) and in turn decreased SP1 and SPARC mRNA and protein levels in Kasumi-1 cells (Figure 8, E and F) and in blasts from 3 different patients with primary AML (numbers 6, 10, and 7) (Figure 8, G and H).…”

Section: Sparc Overexpression Ismentioning

confidence: 99%

SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome

et al. 2014

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Aberrant expression of the secreted protein, acidic, cysteine-rich (osteonectin) (SPARC) gene, which encodes a matricellular protein that participates in normal tissue remodeling, is associated with a variety of diseases including cancer, but the contribution of SPARC to malignant growth remains controversial. We previously reported that SPARC was among the most upregulated genes in cytogenetically normal acute myeloid leukemia (CN-AML) patients with gene-expression profiles predictive of unfavorable outcome, such as mutations in isocitrate dehydrogenase 2 (IDH2-R172) and overexpression of the oncogenes brain and acute leukemia, cytoplasmic (BAALC) and v-ets erythroblastosis virus E26 oncogene homolog (ERG). In contrast, SPARC was downregulated in CN-AML patients harboring mutations in nucleophosmin (NPM1) that are associated with favorable prognosis. Based on these observations, we hypothesized that SPARC expression is clinically relevant in AML. Here, we found that SPARC overexpression is associated with adverse outcome in CN-AML patients and promotes aggressive leukemia growth in murine models of AML. In leukemia cells, SPARC expression was mediated by the SP1/NF-κB transactivation complex. Furthermore, secreted SPARC activated the integrinlinked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent β-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-κB complex resulted in SPARC downregulation and leukemia growth inhibition. Together, our data indicate that evaluation of SPARC expression has prognosticative value and SPARC is a potential therapeutic target for AML.

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Section: Sparc Overexpression Ismentioning

confidence: 99%

SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome

et al. 2014

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“…) mutations (termed PTD/ITD mice) develop de novo AML with 100% penetrance (28). These PTD/ITD mice were crossed with Rag2 -/-Il2rg -/-mice to produce PTD/ITD/Rag GC KO mice; all died from leukemia as validat- what impact the leukemic environment might have on NK cell homeostasis.…”

Section: Itd/wtmentioning

confidence: 99%

MicroRNA-29b mediates altered innate immune development in acute leukemia

Mundy-Bosse¹,

Scoville²,

Chen³

et al. 2016

Journal of Clinical Investigation

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“…Data from murine models and human AML cases suggest that a single mutation is not sufficient to cause AML [12]. For instance, the RUNX-RUNX1T1 and CBFB-MYH11 chimeric oncogenes, resulting from t(8;21) and inv(16)t(16;16) respectively, block myeloid differentiation in murine models but they do not cause an overt leukemic phenotype.…”

Section: Mechanism Of Leukemogenesismentioning

confidence: 99%

“…A multivariable analysis that did not include other molecular genetic markers revealed MLL-PTD status as the only prognostically significant factor for CR duration [85]. Several studies revealed that MLL has been associated with a poor prognosis alone and when associated with FLT3-ITD [12].…”

Section: Mll Prognostic Relevancementioning

confidence: 99%

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Distinct Gene Mutations, their Prognostic Relevance and Molecularly Targeted Therapies in Acute Myeloid Leukemia (AML)

Tayyab¹

2014

J Cancer Sci Ther

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Acquired genetic alterations which include balanced and unbalanced chromosome aberrations and submicroscopic gene mutations and changes in gene expression strongly influenced by pretreatment clinical features and prognosis of adults patients with acute myeloid leukemia (AML). Cytogenetic profiling separate AML patients into three broad prognostic groups: favorable, intermediate and adverse. The cytogenetic risk classifications vary to some extent for younger adult patients and for those aged 60 years or older. In many cases, patients with specific cytogenetic rearrangement such as those with a normal karyotype or those with either RUNX1-RUNX1T1 or CBFB-MYH11 feature of core-binding factor (CBF) can be further subdivided into prognostic categories depend on the presence or absence of specific gene mutations or changes in gene expression. Advancement in the understanding of cancer genetic and discovery of recurrent mutations in AML provide opportunity to develop targeted therapies and improve the clinical outcome. The identified gene mutations, mainly targetable lesions are gain of function mutations of JAK2 and cKIT and FLT3 in APL have been associated with clinical features and/ or outcome of patients with these AML subtypes. These data emphasize the significance of genetic testing for common translocations for diagnosis, prognosis and increasingly targeted therapy in acute leukemia. Notably, these several molecular genetic alterations constitute a variety of diverse new targets for salvage therapies. These approaches intend to develop targeted treatment concepts that depend on interference with molecular genetics or epigenetic mechanisms. This report provides an overview on characteristic gene mutations, discuss their biological functions and Prognostic significance, which serve as basis for selected therapy approaches now or might represent options for such approaches in the future and expected to have a role in treating AML subtypes with characteristic molecular alterations.

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Eradicating acute myeloid leukemia in a MllPTD/wt:Flt3ITD/wt murine model: a path to novel therapeutic approaches for human disease

Cited by 31 publications

References 28 publications

SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome

SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome

MicroRNA-29b mediates altered innate immune development in acute leukemia

Distinct Gene Mutations, their Prognostic Relevance and Molecularly Targeted Therapies in Acute Myeloid Leukemia (AML)

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