Expression of IAP-family proteins in adult acute mixed lineage leukemia (AMLL)

Nakagawa, Yasunori; Hasegawa, Maki; Kurata, Morito; Yamamoto, Kouhei; Abe, Shinya; Inoue, Midori; Takemura, Tamiko; Hirokawa, Katsuíku; Suzuki, Kenshi; Kitagawa, Masanobu

doi:10.1002/ajh.20285

Cited by 37 publications

(26 citation statements)

References 36 publications

(42 reference statements)

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“…The exact role of IAPs in acute leukemia is complicated by the fact that they have been found to display variable expression and to play different roles in chemosensitivity and chemoresistance. IAP expression, determined by quantitative reverse transcription-PCR, was found to be higher in drug-resistant adult acute mixed lineage leukemia (AMLL) than in ALL and AML cells, and the expression of survivin, NAIP, and XIAP was higher in AMLL than ALL (44). Other investigators found XIAP and c-IAP-1 to be differentially expressed among AML patients with an absence of NAIP mRNA (45).…”

Section: Molecular Cancer Therapeutics 1957mentioning

confidence: 97%

Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells

Weisberg

Kung

Wright

et al. 2007

Molecular Cancer Therapeutics

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Members of the inhibitor of apoptosis protein (IAP) family play a role in mediating apoptosis. Studies suggest that these proteins may be a viable target in leukemia because they have been found to be variably expressed in acute leukemias and are associated with chemosensitivity, chemoresistance, disease progression, remission, and patient survival. Another promising therapeutic target, FLT3, is mutated in about one third of acute myelogenous leukemia (AML) patients; promising results have recently been achieved in clinical trials investigating the effects of the protein tyrosine kinase inhibitor PKC412 on AML patients harboring mutations in the FLT3 protein. Of growing concern, however, is the development of drug resistance resulting from the emergence of point mutations in targeted tyrosine kinases used for treatment of acute leukemia patients. One approach to overriding resistance is to combine structurally unrelated inhibitors and/or inhibitors of different signaling pathways. The proapoptotic IAP inhibitor, LBW242, was shown in proliferation studies done in vitro to enhance the killing of PKC412-sensitive and PKC412-resistant cell lines expressing mutant FLT3 when combined with either PKC412 or standard cytotoxic agents (doxorubicin and Ara-c). In addition, in an in vivo imaging assay using bioluminescence as a measure of tumor burden, a total of 12 male NCr-nude mice were treated for 10 days with p.o. administration of vehicle, LBW242 (50 mg/kg/day), PKC412 (40 mg/kg/day), or a combination of LBW242 and PKC412; the lowest tumor burden was observed in the drug combination group. Finally, the combination of LBW242 and PKC412 was sufficient to override stromal-mediated viability signaling conferring resistance to PKC412. [Mol Cancer Ther 2007;6(7):1951–61]

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Section: Molecular Cancer Therapeutics 1957mentioning

confidence: 97%

Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells

Weisberg

Kung

Wright

et al. 2007

Molecular Cancer Therapeutics

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“…This may suggest that cross resistance more likely developed in BAL patients than in AML or ALL patients, causing a poor response to treatment and short survival period. Nakagawa et al 23 found that the overall expression levels of inhibitor of apoptosis protein (IAP)-family proteins in BAL bone marrow cells were higher than those in control, AML, and ALL cells. These results partly supported our observations.…”

Section: Discussionmentioning

confidence: 99%

Clinical and biological characteristics of adult biphenotypic acute leukemia in comparison with that of acute myeloid leukemia and acute lymphoblastic leukemia: a case series of a Chinese population

Xu¹,

Wang²,

Lu³

et al. 2009

Haematologica

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BackgroundBiphenotypic acute leukemia is a rare disorder that is difficult to diagnose. It displays features of both myeloid and lymphoid lineage. There is still a lack of studies in biphenotypic acute leukemia in a Chinese population. We present here a comprehensive investigation of the clinical and biological characteristics, and outcome of biphenotypic acute leukemia in our hospital in over a seven year period. Design and MethodsWe retrospectively analyzed 452 adult acute leukemia patients diagnosed according to French-American-British (FAB) classification and biphenotypic acute leukemia diagnosed according to European Group for the Immunological Characterization of Leukemias (EGIL) classification, respectively. Biological characteristics, response to treatment, and outcome were examined in biphenotypic acute leukemia patients and compared with that in acute myeloid leukemia and acute lymphoblastic leukemia patients with complete follow-up profiles diagnosed in the same period. ResultsOf 452 acute leukemia patients, 21 cases (4.6%) were diagnosed as biphenotypic acute leukemia. Among them, 14 (66.7%) were B lymphoid and myeloid, 5 (23.8%) were T lymphoid and myeloid, one (4.8%) was T/B lymphoid and one (4.8%) was trilineage differentiation. When compared with acute myeloid leukemia and acute lymphoblastic leukemia, patients with biphenotypic acute leukemia showed significantly higher incidence of CD34 antigen expression, unfavorable karyotypes, and extramedullary infiltration (p<0.05). In this cohort of patients with biphenotypic acute leukemia, t(9;22) was the most common abnormality in chromosome structure. The median disease-free survival and overall survival in biphenotypic acute leukemia patients was five months and ten months, respectively, significantly shorter than those in acute myeloid leukemia and acute lymphoblastic leukemia patients (p<0.05). ConclusionsThe prognosis of biphenotypic acute leukemia patients is poor when compared with de novo acute myeloid leukemia or acute lymphoblastic leukemia. Biphenotypic acute leukemia patients showed a much higher incidence of CD34 antigen expression, complex abnormal karyotype, extramedullary infiltration, relapse, and resistance to therapy after relapse.Key words: biphenotypic leukemia, immunophenotype, cytogenetics, prognosis. Haematologica 2009;94:919-927.doi:10.3324/haematol.2008 This is an open-access paper.

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“…60 In adult acute mixed-lineage leukemia, higher expression levels of XIAP and survivin were detected, compared with their expression levels in ALL, indicating that higher levels of several IAP proteins may contribute to the chemotherapy-resistant nature of this type of leukemia. 61 Immunohistochemical analysis of XIAP in diffuse large B-cell lymphoma showed that XIAP overexpression occurred in 55% of the diffuse large B-cell lymphomas and was significantly associated with adverse clinical outcome. 62 Moreover, elevated c-IAP2 mRNA levels were detected in mature neutrophils from a patient with chronic neutrophilic leukemia, but not in neutrophils from patients with chronic myelogenous leukemia.…”

mentioning

confidence: 99%

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

Fulda

2012

Leukemia

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Resistance to apoptosis is one of the hallmarks of human cancers and contributes to the insensitivity of many cancers to commonly used treatment approaches. Inhibitor of apoptosis (IAP) proteins, a family of anti-apoptotic proteins, have an important role in evasion of apoptosis, as they can both block apoptosis-signaling pathways and promote survival. High expression of IAP proteins is observed in multiple cancers, including hematological malignancies, and has been associated with unfavorable prognosis and poor patients' outcome. Therefore, IAP proteins are currently considered as promising molecular targets for therapy. Indeed, drug-discovery approaches over the last decade aiming at neutralizing IAP proteins have resulted in the generation of small-molecule inhibitors or antisense oligonucleotides that demonstrated in vitro and in vivo antitumor activities in preclinical studies. As some of these strategies have already entered the stage of clinical evaluation, for example, in leukemia, an update on this promising molecular-targeted strategy to interfere with apoptotic pathways is of broad interest.

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Expression of IAP-family proteins in adult acute mixed lineage leukemia (AMLL)

Cited by 37 publications

References 36 publications

Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells

Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells

Clinical and biological characteristics of adult biphenotypic acute leukemia in comparison with that of acute myeloid leukemia and acute lymphoblastic leukemia: a case series of a Chinese population

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

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