Inducing apoptosis in chemotherapy‐resistant B‐lineage acute lymphoblastic leukaemia cells by targeting HSPA5, a master regulator of the anti‐apoptotic unfolded protein response signalling network

Uckun, Fatih M.; Qazi, Sanjive; Ozer, Zahide; Garner, Amanda L.; Pitt, Jason J.; Ma, Hong; Janda, Kim D.

doi:10.1111/j.1365-2141.2011.08671.x

Cited by 72 publications

(68 citation statements)

References 54 publications

(151 reference statements)

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“…In agreement with PI3K/AKT as an effector for cytosine arabinoside (AraC) resistance in leukemia, 18 we observed that manipulation of GRP78 expression level alters the sensitivity of human leukemic cells to AraC-induced apoptosis. These, coupled with the emerging association of elevated GRP78 expression in leukemic blasts of adult patients and early relapse in childhood leukemia reported here and by others, [19][20][21] suggest that GRP78 is a novel therapeutic target for leukemia. An Inside Blood analysis of this article appears at the front of this issue.…”

supporting

confidence: 68%

“…Recently, it is reported that resistance of B-ALL cells to the anti-leukemic drug vincristine was suppressed by (Ϫ)-epigallocatechin gallate, which inhibits the antiapoptotic function of GRP78 by targeting to its ATP-binding domain. 21,45 Furthermore, chemoresistant B-ALL cells underwent apoptosis when exposed to a doxorubicin-conjugated penetrating cyclic anti-GRP78 peptide targeting cell surface GRP78. 21 Although the role of GRP78 in human leukemia and recurrence remains to be determined, emerging evidence suggests elevated Grp78 expression in patient leukemic blasts.…”

Section: Discussionmentioning

confidence: 99%

“…21 Extending these findings, we analyzed Grp78 mRNA and protein levels from mononuclear cells purified from the BM or peripheral of patients diagnosed with AML, chronic myeloid leukemia (CML), ALL, and chronic lymphocytic leukemia (CLL). We observed that compared with normal controls, Grp78 mRNA and protein levels are generally elevated at various levels in multiple types of adult patient leukemic blasts, notably AML ( Figure 7A-B).…”

Section: Expression Of Grp78 In Patient Leukemic Blasts and Associatimentioning

confidence: 99%

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Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling

Wey

Luo

Tseng

et al. 2012

Blood

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Traditionally, GRP78 is regarded as protective against hypoxia and nutrient starvation prevalent in the microenvironment of solid tumors; thus, its role in the development of hematologic malignancies remains to be determined. To directly elucidate the requirement of GRP78 in leukemogenesis, we created a biallelic conditional knockout mouse model of GRP78 and PTEN in the hematopoietic system. Strikingly, heterozygous knockdown of GRP78 in PTEN null mice is sufficient to restore the hematopoietic stem cell population back to the normal percentage and suppress leukemic blast cell expansion. AKT/mTOR activation in PTEN null BM cells is potently inhibited by Grp78 heterozygosity, corresponding with suppression of the PI3K/AKT pathway by GRP78 knockdown in leukemia cell lines. This is the first demonstration that GRP78 is a critical effector of leukemia progression, at least in part through regulation of oncogenic PI3K/AKT signaling. In agreement with PI3K/AKT as an effector for cytosine arabinoside resistance in acute myeloid leukemia, overexpression of GRP78 renders human leukemic cells more resistant to cytosine arabinoside-induced apoptosis, whereas knockdown of GRP78 sensitizes them. These, coupled with the emerging association of elevated GRP78 expression in leukemic blasts of adult patients and early relapse in childhood leukemia, suggest that GRP78 is a novel therapeutic target for leukemia. (Blood. 2012;119(3):817-825) IntroductionOne of the most frequently mutated tumor suppressor genes in human cancer is PTEN (phosphatase and tension homolog deleted on chromosome 10), which encodes for a nonredundant, plasmamembrane lipid phosphatase that antagonizes the phosphatidylinositol-3-kinase (PI3K) signaling pathway. 1,2 On loss of PTEN, the PI3K/AKT signaling pathway is activated, leading to promotion of cell survival, proliferation, and angiogenesis, as well as activation of the mTOR and S6 kinases, resulting in enhanced protein translation commonly observed in cancers. 3 PTEN also has a role in the maintenance of the hematopoietic stem cells (HSCs), as shown by ablation of PTEN function in adult HSCs through crossing of polyinosine-polycytidine (pIpC)-inducible Mx-1-Cre transgenic mouse line 4 with a Pten flox/flox (Pten f/f ) mouse line. 5 Induced Cre expression in postnatal mice exhausted normal HSCs and promoted excessive proliferation of leukemogenic stem cells, resulting in the development of myeloproliferative disorders (MPDs) and eventually leukemia. 6,7 These studies further showed that the mTOR inhibitor rapamycin effectively suppressed growth of the leukemogenic stem cells and prevented exhaustion of normal HSCs. Furthermore, recent studies have shown that PTEN is down-regulated by BCR-ABL in leukemic stem cells, and PI3K and AKT play critical roles in BCR-ABL-induced leukemia in mice. 8,9 Thus, inhibition of the PTEN/AKT/mTOR pathway not only can suppress solid tumor growth but could also represent a novel therapeutic strategy against stem cell disorders that are leukemogenic in nature.GRP78, also ref...

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supporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Expression Of Grp78 In Patient Leukemic Blasts and Associatimentioning

confidence: 99%

See 1 more Smart Citation

Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling

Wey

Luo

Tseng

et al. 2012

Blood

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“…The function of GRP78 in the hematopoietic system is just emerging, however, recent study clearly revealed involvement of GRP78 in hematopoietic stem cell survival and lymphogenesis (Wey et al 2012a). In addition, it has been shown that GRP78 expression is up-regulated in various forms of human leukaemia and implicated as causative factor for therapeutic resistance and early relapse (Tanimura et al 2009;Rosati et al 2010;Uckun et al 2011;Wey et al 2012b). In our experiments, we have detected GRP78 to be expressed in non-treated HL-60 cells and treatment of the cells with NaBu for 48 hours was associated with decrease of GRP78 level.…”

Section: Discussionsupporting

confidence: 53%

ABT-737 accelerates butyrate-induced death of HL-60 cells. Involvement of mitochondrial apoptosis pathway

Stefanikova

Kliková²,

Hatok³

et al. 2013

gpb

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Abstract. The aim of presented study was to determine effect of NaBu in combination with ABT-737 on cell survival of leukemic cell line HL-60. In addition, analysis of molecular mechanism of NaBu action with a focus on mitochondrial apoptosis was performed. Both NaBu and ABT-737 are inducing death of HL-60 cells with different kinetics. ABT-737-induced cell death is fast while NaBu-induced death preceded by cell cycle arrest in G2 phase is rather slow. Cell viability was significantly decreased after 48 hours of incubation with 2 and 5 mmol/l of NaBu while it was significantly decreased after 24 hours of incubation with 1 μmol/l of ABT-737 combined with 2 and 5 mmol/l of NaBu. Incubation of HL-60 cells with NaBu was associated with increased level of pro-apoptotic protein BIM EL and decreased levels of anti-apoptotic proteins of Bcl-2 family as well as GRP78 involved in ER stress signalling. It seems that ABT-737 accelerates NaBu-induced death of HL-60 cells due to mitochondrial apoptosis resulting from ABT-737-mediated inhibition of functions and NaBu-induced decrease of the levels of anti-apoptotic Bcl-2 family proteins as well as due to accelerated decrease of GRP78 observed after the treatment of cells with combination of NaBu and ABT-737. The effect of combination of both drugs on survival of HL-60 cells seems to be synergistic at high concentrations of NaBu (2 and 5 mmol/) while it is rather antagonistic at concentrations of NaBu less than 1 mmol/l. Finally, it might be assumed that NaBu is capable to induce cell death with mechanisms independent from mitochondrial apoptosis.

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“…For example, the immunoglobulin heavy chain binding protein, BIP/HSPA5, a pivotal component of the prosurvival axis of the unfolded protein response signaling network, is abundantly expressed in relapsed B-cell ALL and has been proposed as a chemotherapy-resistance biomarker. 40 A murine model also detailed that obesity might be a factor in resistance, with ALL cells preferentially migrating to a proposed protective microenvironment within adipose cells. 41 A number of Phase I and II clinical trials of novel agents are currently underway to investigate novel targeted therapies for relapsed ALL to improve outcomes.…”

Section: Treatment Of Relapsed Philadelphia-negative Allmentioning

confidence: 99%

Treating relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: liposome-encapsulated vincristine

Davis¹,

Farag

2013

IJN

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Inducing apoptosis in chemotherapy‐resistant B‐lineage acute lymphoblastic leukaemia cells by targeting HSPA5, a master regulator of the anti‐apoptotic unfolded protein response signalling network

Cited by 72 publications

References 54 publications

Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling

Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling

ABT-737 accelerates butyrate-induced death of HL-60 cells. Involvement of mitochondrial apoptosis pathway

Treating relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: liposome-encapsulated vincristine

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