Mechanistic role of heat shock protein 70 in Bcr-Abl–mediated resistance to apoptosis in human acute leukemia cells

Guo, Fei; Sigua, Celia; Bali, Purva; George, Prince; Fiskus, Warren; Scuto, Anna; Annavarapu, Srinivas; Mouttaki, Abdelmoughite; Sondarva, Gautam; Wei, Sheng; Wu, Jie; Djeu, Julie Y.; Bhalla, Kapil N.

doi:10.1182/blood-2004-05-2041

Cited by 158 publications

(157 citation statements)

References 54 publications

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“…Changes in Hsp70 expression have been previously shown to confer resistance to apoptosis in leukemic cells expressing the Bcr-Abl oncogene. 39 Unexpectedly, we bring evidence for the first time of a possible link between STAT5 and the oxidative metabolism in pre-B cells. This is suggested by the downregulation of transaldolase, GSH synthetase DJ-1 and Proteins 1-4 expression and the upregulation of QPRTase and DDAH2 expression.…”

Section: Discussionmentioning

confidence: 61%

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

Cholez

Debuysscher

Bourgeais³

et al. 2012

Leukemia

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,5,6 STAT5 transcription factors are involved in normal B lymphocyte development and in leukemogenesis. We show that the inhibition of STAT5A expression or activity in the NALM6, 697 and Reh leukemic pre-B cell lines, results in a higher spontaneous apoptosis and an increased FAS-induced cell death. However, the molecular mechanisms underlying the altered pre-B cell survival are unclear. We used a proteomic approach to identify proteins that are differentially regulated in cells expressing (NALM6D5A) or not a dominant negative form of STAT5A. Among the 14 proteins identified, six were involved in the control of the oxidative stress like glutathione (GSH) synthetase and DJ-1. Accordingly, we showed increased levels of reactive oxygen species (ROS) in NALM6D5A cells and suppression of the increased sensitivity to Fas-mediated apoptosis by the GSH tripeptide. Similar results were observed when NALM6 cells were treated with TAT-STAT5D5A fusion proteins or STAT5A shRNA. In addition, the 697 and Reh pre-B cells were found to share number of molecular changes observed in NALM6D5A cells including ROS generation, following inhibition of STAT5 expression or function. Our results point out to a hitherto undescribed link between STAT5 and oxidative stress and provide new insights into STAT5 functions and their roles in leukemogenesis.Leukemia ( INTRODUCTIONThe signal transducer and activator of transcription factors STAT5A and STAT5B are two closely related STAT family members that play a major role in cytokine and growth factor signaling. 1 Number of studies have demonstrated that STAT5 plays a crucial role in hematopoiesis. In particular, the knockout mice models (Stat5a/ b DN/DN and Stat5a/b null/null ) have pointed up the important role of STAT5 in hematopoietic cell development. 2,3 These mice have multiple hematopoietic defects, which affect the proliferation and/ or survival of both myeloid and lymphoid lineages, including B-cell development. 4 In the Stat5a/b null/null mice, the precursor B-cell compartment is substantially reduced presumably due to an inability of progenitor B cells to proliferate in response to interleukin-7 (IL-7). However, differentiation towards mature B cells seems to be unaffected. 5,6 STAT5 is also involved in the regulation of IL-7-dependent germline transcription, histone acetylation and DNA recombination of distal VH gene segments, which are the hallmark of B lymphocyte development. 7 Accordingly, a constitutively active form of STAT5B in IL-7R À / À mice, is sufficient to restore B-cell development. 8 However, the instructive role for STAT5 and IL-7-R signaling in early B-cell development has been controversial in a mouse model of conditional mutagenesis of STAT5. 9 This model showed that the main role of IL-7-mediated activation of STAT5 is to promote pro-B-cell survival via Mcl1 and to prevent premature rearrangements of the immunoglobulin-k light-chain locus (Igk) by binding to the

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Section: Discussionmentioning

confidence: 61%

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

Cholez

Debuysscher

Bourgeais³

et al. 2012

Leukemia

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“…[8][9][10][11][12][13][14][15][16][17][18][19][20] Increasing evidence has shown that specific inhibition of HSP90 in neoplastic cells can lead to cell cycle arrest and apoptosis. [8][9][10][11][12][13][14][15][16][17][18][19][20] No previous study, however, has systematically surveyed HSP90 expression in a variety of NHL types as defined in the WHO classification. Thus, the aim of this study was to assess for HSP90 expression in various types of B-and T-NHL, in light of the potential utility of HSP90 inhibitors in the treatment of patients with NHL.…”

Section: Discussionmentioning

confidence: 99%

“…14 Recently, in vitro studies have shown that treatment of solid tumors and hematological malignancies with a naturally occurring antibiotic, geldanamycin, and its derivative, 17-AAG, inhibits HSP90 activity through blocking ATP-binding sites of the HSP90-partner complex, with subsequent proteosomal degradation and/or dephosphorylation of client proteins. [10][11][12][13][14][15][16][17][18][19][20] These HSP inhibitors act mainly by occupying the binding site for the client protein within the HSP90-multichaperone complex and, by blocking this step, these derivatives enhance protein destabilization with subsequent shortening of protein half-life and eventual proteosomal degradation. 9 Based on the promising results of preclinical studies, [10][11][12][13][14][15][16][17][18][19][20] several phase I clinical trials with 17-AAG have been initiated in the United States and United Kingdom for patients with hematological malignancies, and solid tumors including breast, prostate and kidney cancers.…”

Section: Discussionmentioning

confidence: 99%

“…9 Via the N-terminal domain, HSP90 serves as a molecular chaperone for many client proteins that are involved in oncogenesis, for example, NF-kappa B, BCR-ABL, NPM-ALK, AKT and mutated p53. [8][9][10][11][12][13][14][15][16][17][18][19][20] As these client proteins are involved in a number of pathways that are critical to the survival of neoplastic cells, HSP90 is an attractive target for inhibition because many pathways can be blocked simultaneously. It therefore follows that HSP90 inhibitors could be active against many tumor types.…”

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confidence: 99%

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Expression of heat-shock protein-90 in non-Hodgkin's lymphomas

et al. 2005

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Heat-shock protein-90 (HSP90) inhibitors are currently being used in phase I clinical trials for treating patients with a variety of neoplasms including lymphomas. Using immunohistochemical methods, we assessed for HSP90 expression in 412 cases of non-Hodgkin's lymphoma. In B-cell lymphomas, HSP90 was moderately to strongly expressed in all cases of Burkitt's lymphoma (5/5, 100%), and in subsets of follicular lymphoma (17/28, 61%), diffuse large B-cell lymphoma (27/46, 59%), nodal marginal zone B-cell lymphoma (6/16, 38%), plasma cell neoplasms (14/39, 36%), small lymphocytic lymphoma/chronic lymphocytic leukemia (3/9, 33%), mantle cell lymphoma (12/38, 32%) and lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (3/10, 30%). HSP90 was weakly expressed in six of 14 (43%) cases of extranodal marginal zone B-cell lymphoma of mucosaassociated lymphoid tissue. In T-cell lymphomas, HSP90 was moderately to strongly expressed in subsets of anaplastic large-cell lymphoma (14/24, 58%; 9/12 ALK þ and 5/12 ALKÀ), precursor-T-cell lymphoblastic leukemia/lymphoma (20/65, 31%), unspecified peripheral T-cell lymphoma (8/43, 23%) and angioimmunoblastic T-cell lymphoma (2/17, 12%). HSP90 was weakly expressed in seven of 58 (12%) cases of mycosis fungoides. We conclude that HSP90 is commonly expressed in a subset of many types of B-and T-cell lymphoma. These data suggest that many lymphoma types are suitable targets for modulation of HSP90 activity, and that HSP90 inhibitors are a potential investigational therapy for lymphoma patients.

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“…hTid1 interacts with the chaperone molecules Hsc70 and Hsp70 (40,55). Interestingly, it was previously shown that overexpression of Hsp70 protein in leukemic cells increases the expression of STAT5 (57). Thus, it is likely that hTid1 may act on STAT5b expression via interaction with Hsp70, a hypothesis that awaits further experiments.…”

Section: Discussionmentioning

confidence: 97%

The Tumor Suppressor hTid1 Inhibits STAT5b Activity via Functional Interaction

Dhennin‐Duthille¹,

Nyga²,

Yahiaoui³

et al. 2011

Journal of Biological Chemistry

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STAT5a and -5b (signal transducers and activators of transcription 5a and 5b) proteins play an essential role in hematopoietic cell proliferation and survival and are frequently constitutively active in hematologic neoplasms and solid tumors. Because STAT5a and STAT5b differ mainly in the carboxylterminal transactivation domain, we sought to identify new proteins that bind specifically to this domain by using a bacterial two-hybrid screening. We isolated hTid1, a human DnaJ protein that acts as a tumor suppressor in various solid tumors. hTid1 interacts specifically with STAT5b but not with STAT5a in hematopoietic cell lines. This interaction involves the cysteine-rich region of the hTid1 DnaJ domain. We also demonstrated that hTid1 negatively regulates the expression and transcriptional activity of STAT5b and suppresses the growth of hematopoietic cells transformed by an oncogenic form of STAT5b. Our findings define hTid1 as a novel partner and negative regulator of STAT5b.STAT transcription factors play a central role in cytokinedependent survival, proliferation, and differentiation of a large spectrum of cells. Following cytokine addition, STAT proteins become tyrosine-phosphorylated and subsequently dimerize, forming homo-or heterodimers, and translocate into the nucleus, where they bind to specific elements in the promoter of target genes and activate transcription (1). The STAT protein family comprises seven members, including the two closely related STAT5a and STAT5b molecules (2, 3). Mice in which stat5a and stat5b genes were deleted revealed redundant and specific functions of both proteins. stat5a

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Mechanistic role of heat shock protein 70 in Bcr-Abl–mediated resistance to apoptosis in human acute leukemia cells

Cited by 158 publications

References 54 publications

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

Expression of heat-shock protein-90 in non-Hodgkin's lymphomas

The Tumor Suppressor hTid1 Inhibits STAT5b Activity via Functional Interaction

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