HOXA/PBX3 knockdown impairs growth and sensitizes cytogenetically normal acute myeloid leukemia cells to chemotherapy

Dickson, Glenda J.; Liberante, Fabio G.; Kettyle, Laura M.; O'Hagan, Kathleen; Finnegan, Damian; Bullinger, Lars; Geerts, Dirk; McMullin, Mary Frances; Lappin, Terry R.J.; Mills, Ken I.; Thompson, Alexander

doi:10.3324/haematol.2012.079012

Cited by 44 publications

(45 citation statements)

References 49 publications

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“…In addition, more than 210 genes are significantly repressed by both MLL-fusion proteins and the PBX3/MEIS1 combination; although these genes are also repressed by HOXA9 alone or together with MEIS1 or PBX3 , the repression degrees are much more moderate. Therefore, despite the close relationship between HOXA9 , MEIS1 and PBX3 (18, 24-27), only the PBX3/MEIS1 combination, but not the HOXA9/MEIS1 or HOXA9/PBX3 combination (or HOXA9 alone), can resemble MLL-fusion proteins in inducing critical transcriptional programs. Further systematic studies are warranted in the future to decipher the underlying molecular mechanism(s).…”

Section: Discussionmentioning

confidence: 99%

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PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease

Chen

et al. 2016

Cancer Research

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Overexpression of HOXA/MEIS1/PBX3 homeobox genes is the hallmark of mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML). HOXA9 and MEIS1 are considered to be the most critical targets of MLL fusions and their co-expression rapidly induces AML. MEIS1 and PBX3 are not individually able to transform cells and were therefore hypothesized to function as cofactors of HOXA9. However, in this study we demonstrate that co-expression of PBX3 and MEIS1 (PBX3/MEIS1), without ectopic expression of a HOX gene, is sufficient for transformation of normal mouse hematopoietic stem/progenitor cells in vitro. Moreover, PBX3/MEIS1 overexpression also caused AML in vivo, with a leukemic latency similar to that caused by forced expression of MLL-AF9, the most common form of MLL fusions. Furthermore, gene expression profiling of hematopoietic cells demonstrated that PBX3/MEIS1 overexpression, but not HOXA9/MEIS1, HOXA9/PBX3 or HOXA9 overexpression, recapitulated the MLL-fusion-mediated core transcriptome, particularly upregulation of the endogenous Hoxa genes. Disruption of the binding between MEIS1 and PBX3 diminished PBX3/MEIS1-mediated cell transformation and HOX gene upregulation. Collectively, our studies strongly implicate the PBX3/MEIS1 interaction as a driver of cell transformation and leukemogenesis, and suggest that this axis may play a critical role in the regulation of the core transcriptional programs activated in MLL-rearranged and HOX-overexpressing AML. Therefore, targeting the MEIS1/PBX3 interaction may represent a promising therapeutic strategy to treat these AML subtypes.

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Section: Discussionmentioning

confidence: 99%

“…We showed further that PBX3, rather than PBX1 or PBX2, is an important cofactor of HOXA9 in cytogenetically abnormal AML and their co-expression can cause development of rapid AML in mice (26). The prognostic impact and essential oncogenic role of PBX3 have also been observed in cytogenetic normal AML (27). …”

Section: Introductionmentioning

confidence: 98%

PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease

Chen

et al. 2016

Cancer Research

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“…17 Interest in Pbx proteins as Hox cofactors was rekindled with the discovery that another Pbx family member, Pbx3, cooperated with Hoxa9 in experimental leukemogenesis and that knock-down of Pbx3 could impair transformation induced by Hoxa9. 18,19 In a clinical setting PBX3 expression was an independent predictor of poor survival in leukemia patients and the presence of PBX3 was well correlated with HOX status within leukemic cells. Yet, the molecular mechanism behind these in vivo observations was not investigated further.…”

Section: Introductionmentioning

confidence: 99%

Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemia

García-Cuéllar¹,

Steger²,

E³

et al. 2015

Haematologica

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Hox homeobox transcription factors drive leukemogenesis efficiently only in the presence of Meis or Pbx proteins. Here we show that Pbx3 and Meis1 need to dimerize to support Hox-induced leukemia and we analyze the molecular details of this cooperation. In the absence of Pbx3, Meis1 was highly unstable. As shown by a deletion analysis Meis1 degradation was contingent on a motif coinciding with the Pbx-binding domain. Either deletion of this sequence or binding to Pbx3 prolonged the half-life of Meis1 by preventing its ubiquitination. Meis1 break-down could also be blocked by inhibition of the ubiquitin proteasome system, indicating tight post-transcriptional control. In addition, Meis1 and Pbx3 cooperated genetically as overexpression of Pbx3 induced endogenous Meis1 transcription. These functional interactions translated into in vivo activity. Blocking Meis1/Pbx3 dimerization abrogated the ability to enhance proliferation and colony-forming cell numbers in primary cells transformed by Hoxa9. Furthermore, expression of Meis1 target genes Flt3 and Trib2 was dependent on Pbx3/Meis1 dimerization. This correlated with the requirement of Meis1 to bind Pbx3 in order to form high affinity DNA/Hoxa9/Meis1/Pbx3 complexes in vitro. Finally, kinetics and severity of disease in transplantation assays indicated that Pbx3/Meis1 dimers are rate-limiting factors for Hoxa9-induced leukemia. Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemiaMaria-Paz Garcia-Cuellar, Julia Steger, Elisa Füller, Katrin Hetzner, and Robert K. Slany Department of Genetics, Friedrich-Alexander-University, Erlangen, Germany ABSTRACT ments the ability of Meis1 to support Hox-mediated leukemogenesis. We demonstrate that Pbx3 protects Meis1 from proteasomal degradation. Additionally, Pbx3 increases Meis1 affinity for Hoxa9 and it induces endogenous Meis1 transcription. MethodsPlasmids, retroviral constructs, antibodies and cell culture

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“…The human bone marrow stromal cell line, HS5, and the human acute myeloid leukemia cell line, U93779, were obtained from the American Type Culture Collection (Manassas, VA, USA). 293FT and HT1080 cells were acquired in 2012 from Invitrogen (Carlsbad, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes

Lopes

Pereira

Campos

et al. 2017

Sci Rep

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The interaction between the bone marrow microenvironment and malignant hematopoietic cells can result in the protection of leukemia cells from chemotherapy in both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We, herein, characterized the changes in cytokine expression and the function of mesenchymal stromal cells (MSC) in patients with MDS, AML with myelodysplasia-related changes (MRC), a well-recognized clinical subtype of secondary AML, and de novo AML. We observed a significant inhibitory effect of MDS-MSC on T lymphocyte proliferation and no significant differences in any of the cytokines tested. AML-MSC inhibited T-cell proliferation only at a very low MSC/T cell ratio. When compared to the control, AML-MRCderived MSC presented a significant increase in IL6 expression, whereas de novo AML MSC presented a significant increase in the expression levels of VEGFA, CXCL12, RPGE2, IDO, IL1β, IL6 and IL32, followed by a decrease in IL10 expression. Furthermore, data indicate that IL-32 regulates stromal cell proliferation, has a chemotactic potential and participates in stromal cell crosstalk with leukemia cells, which could result in chemoresistance. Our results suggest that the differences between AML-MRC and de novo AML also extend into the leukemic stem cell niche and that IL-32 can participate in the regulation of the bone marrow cytokine milieu.

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HOXA/PBX3 knockdown impairs growth and sensitizes cytogenetically normal acute myeloid leukemia cells to chemotherapy

Abstract: ©2013 Ferrata Storti Foundation. This is an open-access paper.

Cited by 44 publications

References 49 publications

PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease

PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease

Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemia

De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes

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