Notch activation inhibits AML growth and survival: a potential therapeutic approach

Kannan, Sankaranarayanan; Sutphin, Robert M.; Hall, Mandy A; Golfman, Leonard S.; Fang, Wendy; Nolo, Riitta; Akers, Lauren J.; Hammitt, Richard A.; McMurray, John S.; Kornblau, Steven M.; Melnick, Ari; Figueroa, María E.; Zweidler‐McKay, Patrick A.

doi:10.1084/jem.20121527

Cited by 130 publications

(136 citation statements)

References 60 publications

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“…In another study the same authors suggested that caspase-3 activation and PARP inactivation may play a role in prednisolone-and l-asparaginase-induced apoptosis, but are not essential to vincristine-and daunorubicin-induced apoptosis [15]. Kannan et al reported that Notch 1-related transcription factors stimulate higher expression of PARP-1 messenger RNA and thus induce apoptosis in B-ALL cell lines, an effect not seen in T-ALL cell lines [20]. Pottier et al stated that lower SMARCB1 expression increased prednisolone resistance in childhood ALL.…”

Section: Discussionmentioning

confidence: 99%

PARP-1 expression in CD34+ leukemic cells in childhood acute lymphoblastic leukemia: relation to response to initial therapy and other prognostic factors

Kruk¹,

Ociepa²,

Urasiński³

et al. 2015

pjp

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Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that impacts DNA repair and apoptosis. Both experimental and ongoing clinical studies indicate that PARP-1 inhibitors are potent and promising anticancer agents. However, the outcome of treatment with PARP-1 inhibitors depends on the expression of PARP-1 protein in the tumor cells. This study aimed to assess PARP-1 expression in peripheral blood CD34+ leukemic cells before and after 12 hours of prednisone administration as well as the relation between PARP-1 expression and early treatment response to initial therapy and other prognostic factors (immunophenotype, age, initial peripheral blood white blood count [WBC], and risk factor group). The study comprised 43 children with de novo ALL. Cytospins of peripheral blood were stained with mouse anti-CD34-FITC and anti-PARP-1 antibody followed by goat anti-mouse APC-conjugated antibody. DNA was counterstained with PI (propidium iodide). Cellular fluorescence was measured by a laser scanning cytometer. Statistically significant differences in baseline PARP-1 expression with respect to early treatment response (good vs. poor), ALL immunophenotype (ALL B vs. ALL T), age (children < 1 years and > 6 years vs. children 1-6 years), initial WBC (< 20 000/µl vs. ≥ 20 000/µl), and risk factor group (SR vs. IR vs. HR) were not found. PARP-1 expression was increased 12 hours after treatment in poor early treatment responders, whereas it remained statistically unchanged with respect to ALL immunophenotype, age, initial WBC, risk factor group and early treatment response. The overexpression of PARP-1 in poor early treatment responders suggests that it may contribute to treatment failure in this group of children with ALL. Our observation -if confirmed by other studies -may form the rationale for administration of PARP inhibitors in selected subsets of ALL children.

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Section: Discussionmentioning

confidence: 99%

PARP-1 expression in CD34+ leukemic cells in childhood acute lymphoblastic leukemia: relation to response to initial therapy and other prognostic factors

Kruk¹,

Ociepa²,

Urasiński³

et al. 2015

pjp

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“…Indeed, Notch agonists were shown to enhance p53 expression along with BCL2 downregulation and growth inhibition of AML cells. 93 …”

Section: Aml With Chromosomal Translocationsmentioning

confidence: 99%

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

Prokocimer

Molchadsky

Rotter

2017

Blood

136

119

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The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis. While in human solid tumors TP53 is mutated in more than half of cases, TP53 mutations occur in less than one tenth of de novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to nonmutational p53 abnormalities appears to be rather frequent in various AML entities, bearing, presumably, a greater impact than is currently appreciated. Hereby, we advocate assessment of adult AML with respect to coexisting p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function but also on the mechanisms underlying nonmutational wtp53 inactivation, which might be of therapeutic relevance. Patient-specific TP53 genotyping with functional evaluation of p53 protein may contribute significantly to the precise assessment of p53 status in AML, thus leading to the tailoring of a rationalized and precision p53-based therapy. The resolution of the mechanisms underlying p53 dysfunction will better address the p53-targeted therapies that are currently considered for AML. Additionally, a suggested novel algorithm for p53-based diagnostic workup in AML is presented, aiming at facilitating the p53-based therapeutic choices. (Blood. 2017; 130(6):699-712)

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“…FLT3 is already known as a frequently mutated oncogene in AML, whereas the role of NOTCH2 in this disease is not well understood, although decreased NOTCH2 expression has been linked to AML in 2 reports. 35,36 Cloning and sequencing analysis identified several aberrant splice variants of NOTCH2 and FLT3 that resulted from either skipping of $1 exon or activation of cryptic splicing sites. All these splicing alterations created transcripts that encoded proteins, as demonstrated through expression of NOTCH2-Va, NOTCH2-Vb, FLT3-Va, and FLT3-Vb splice variants in HEK293T cells.…”

Section: Discussionmentioning

confidence: 99%

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

Adamia

Bar-Natan

Haibe‐Kains

et al. 2014

Blood

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• Overall, our results suggest that NOTCH2 and FLT3 aberrant splicing is a common event in AML that correlates with disease status and may correlate with disease outcomes. • Selected variants of NOTCH2and FLT3 transcripts were detected in a significant number of AML patients and could be useful as disease markers.Our previous studies revealed an increase in alternative splicing of multiple RNAs in cells from patients with acute myeloid leukemia (AML) compared with CD34 1 bone marrow cells from normal donors. Aberrantly spliced genes included a number of oncogenes, tumor suppressor genes, and genes involved in regulation of apoptosis, cell cycle, and cell differentiation. Among the most commonly mis-spliced genes (>70% of AML patients) were 2, NOTCH2 and FLT3, that encode myeloid cell surface proteins. The splice variants of NOTCH2 and FLT3 resulted from complete or partial exon skipping and utilization of cryptic splice sites. Longitudinal analyses suggested that NOTCH2 and FLT3 aberrant splicing correlated with disease status. Correlation analyses between splice variants of these genes and clinical features of patients showed an association between NOTCH2-Va splice variant and overall survival of patients. Our results suggest that NOTCH2 and FLT3 mis-splicing is a common characteristic of AML and has the potential to generate transcripts encoding proteins with altered function. Thus, splice variants of these genes might provide disease markers and targets for novel therapeutics. (Blood. 2014;123(18):2816-2825

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Notch activation inhibits AML growth and survival: a potential therapeutic approach

Abstract: Activating Notch with a Notch agonist peptide induces apoptosis in AML patient samples.

Cited by 130 publications

References 60 publications

PARP-1 expression in CD34+ leukemic cells in childhood acute lymphoblastic leukemia: relation to response to initial therapy and other prognostic factors

PARP-1 expression in CD34+ leukemic cells in childhood acute lymphoblastic leukemia: relation to response to initial therapy and other prognostic factors

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

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