The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia

Huang, Weiqi; Luan, Chi‐Hao; Hjort, Elizabeth; Bei, Ling; Mishra, Rama K.; Sakamoto, Kathleen M.; Platanias, Leonidas C.; Eklund, Elizabeth A.

doi:10.1038/leu.2016.66

Cited by 14 publications

(29 citation statements)

References 40 publications

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“…Exaggerated granulocytosis is observed during infection in chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMMoL), but the role of emergency granulopoiesis in these diseases is unknown. This may be a useful area of investigation, since CML and CMMoL are characterized by decreased activity of Icsbp; a key activator of FANCC and FANCF transcription (43–45). …”

Section: Discussionmentioning

confidence: 99%

TP53 Haploinsufficiency Rescues Emergency Granulopoiesis in FANCC−/− Mice

Huang

Bei

et al. 2018

The Journal of Immunology

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Emergency (stress) granulopoiesis is an episodic process for production of granulocytes in response to infectious challenge. We previously determined that Fanconi C, a component of the Fanconi DNA-repair pathway, is necessary for successful emergency granulopoiesis. Fanconi Anemia (FA) results from mutation of any gene in this pathway and is characterized by bone marrow failure (BMF) in childhood and clonal progression in adolescence. Although murine FA models exhibit relatively normal steady state hematopoiesis, FANCC−/− mice are unable to mount an emergency granulopoiesis response. Instead, these mice develop BMF and death during repeated, unsuccessful emergency granulopoiesis attempts. In FANCC−/− mice, BMF is associated with extensive apoptosis of hematopoietic stem and progenitor cells through an undefined mechanism. In the current studies, we find TP53 haplo-insufficiency completely rescues emergency granulopoiesis in FANCC−/− mice and protects them from BMF during repeated emergency granulopoiesis episodes. Instead, such recurrent challenges accelerated clonal progression in FANCC−/−TP53+/− mice. In FANCC−/− mice, BMF during multiple emergency granulopoiesis attempts was associated with increasing Atr and p53 activation with each attempt. In contrast, we found progressive attenuation of expression and activity of Atr, and consequent p53 activation and apoptosis, in the bone marrow of FANCC−/−TP53+/− mice during this process. Therefore, activation of Atr, with consequent Fanconi mediated DNA repair or p53-dependent apoptosis, are essential components of emergency granulopoiesis and protect the bone marrow from genotoxic stress during this process.

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Section: Discussionmentioning

confidence: 99%

TP53 Haploinsufficiency Rescues Emergency Granulopoiesis in FANCC−/− Mice

Huang

Bei

et al. 2018

The Journal of Immunology

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“…We investigated Stat3 for activity on the human IRF8 promoter, but did not see an effect of either overexpression or knockdown of this transcription factor (data not shown). Xiap1 is a Calpain substrate of potential interest, since our previous studies identified regulation of Fas-induced apoptosis as a role for Icsbp during myelopoiesis and in leukemogenesis [14, 15, 23]. …”

Section: Discussionmentioning

confidence: 99%

“…For some experiments, cells were transduced with retroviral vectors to express p210 Bcr-abl (in MiGR1 vector), DN-Gas2 (in MSCVpuro vector), or DN-Shp2 (in MSCVneo vector). Replication incompetent retroviral vectors were generated using the Ecopack packaging plasmid, as described [23]. …”

Section: Methodsmentioning

confidence: 99%

“…During normal myelopoiesis, repression of the Fap1 gene ( PTPN13 ) by Icsbp increases sensitivity to Fas-induced apoptosis and facilitates proteasomal degradation of βcatenin as differentiation proceeds [15, 20]. We found that Fap1 inhibition in a murine model of CML delayed emergence of TKI resistance and decreased LSC persistence in vivo , suggesting relevance of Icsbp/Fap1 regulated events [23]. …”

Section: Introductionmentioning

confidence: 99%

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Bcr-abl regulates Stat5 through Shp2, the interferon consensus sequence binding protein (Icsbp/Irf8), growth arrest specific 2 (Gas2) and calpain

Hjort

Huang

et al. 2016

Oncotarget

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Icsbp/Irf8 is an interferon regulatory transcription factor that functions as a suppressor of myeloid leukemias. Consistent with this activity, Icsbp represses a set of genes encoding proteins that promote cell proliferation/survival. One such gene encodes Gas2, a calpain inhibitor. We previously found that increased Gas2-expression in Bcr-abl+ cells stabilized βcatenin; a Calpain substrate. This was of interest, because βcatenin contributes to disease progression in chronic myeloid leukemia (CML). Calpain has additional substrates implicated in leukemogenesis, including Stat5. In the current study, we hypothesized that Stat5 activity in CML is regulated by Gas2/Calpain. We found that Bcr-abl-induced, Shp2-dependent dephosphorylation of Icsbp impaired repression of GAS2 by this transcription factor. The consequent decrease in Calpain activity stabilized Stat5 protein; increasing the absolute abundance of both phospho and total Stat5. This enhanced repression of the IRF8 promoter by Stat5 in a manner dependent on Icsbp, Gas2 and Calpain, but not Stat5 tyrosine phosphorylation. During normal myelopoiesis, increased expression and phosphorylation of Icsbp inhibits Calpain. In contrast, constitutive activation of Shp2 in Bcr-abl+ cells impairs regulation of Gas2/Calpain by Icsbp, aberrantly stabilizing Stat5 and enhancing IRF8 repression. This novel feedback mechanism enhances leukemogenesis by increasing Stat5 and decreasing Icsbp. Bcr-abl targeted tyrosine kinase inhibitors (TKIs) provide long term disease control, but CML is not cured by these agents. Our studies suggest targeting Calpain might be a rational therapeutic approach to decrease persistent leukemia stem cells (LSCs) during TKI-treatment.

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“…This induced Fas-resistance and enhanced transcription of βcatenin target genes, including BIRC5 (encoding Survivin). In a murine model of CML, we determine treatment with Imatinib (IM; a TKI inhibitor) plus a Fap1-blocking peptide prevented chronic phase (CP) relapse or blast crisis (BC) progression, although IM alone did not [12]. And, mice treated with IM plus Fap1-blocking peptide sustained remission after therapy discontinuation, although 60% of mice treated with IM alone relapsed.…”

Section: Introductionmentioning

confidence: 99%

Investigating the role of the innate immune response in relapse or blast crisis in chronic myeloid leukemia

2020

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Chronic myeloid leukemia (CML) is characterized by expression of the tyrosine kinase oncogene, Bcr-abl. Tyrosine kinase inhibitors (TKI) induce prolonged remission in CML, and therapy discontinuation is an accepted approach to patients with reduction in Bcr-abl transcripts of four logs or greater. Half such individuals sustain a therapy free remission, but molecular mechanisms predicting relapse are undefined. We found relative calpain inhibition in CML cells with stabilization of calpain substrates, including βcatenin and Xiap1. Since the Survivin gene is activated by βcatenin, this identified two apoptosisresistance mechanisms. We found that Survivin impaired apoptosis in leukemia stem cells (LSCs) and Xiap1 in CML granulocytes. Consistent with this, we determined treatment with an inhibitor of Survivin, but not Xiap1, prevented relapse during TKI treatment and after therapy discontinuation in a murine CML model. By transcriptome profiling, we identified activation of innate immune response pathways in murine CML bone marrow progenitors. This was increased by TKI treatment alone, but normalized with addition of a Survivin inhibitor. We found that activation of the innate immune response induced rapid blast crisis in untreated CML mice, and chronic phase relapse during a TKI discontinuation attempt. These results suggest that extrinsic stress exerts adverse effects on CML-LSCs.

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The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia

Cited by 14 publications

References 40 publications

TP53 Haploinsufficiency Rescues Emergency Granulopoiesis in FANCC−/− Mice

TP53 Haploinsufficiency Rescues Emergency Granulopoiesis in FANCC−/− Mice

Bcr-abl regulates Stat5 through Shp2, the interferon consensus sequence binding protein (Icsbp/Irf8), growth arrest specific 2 (Gas2) and calpain

Investigating the role of the innate immune response in relapse or blast crisis in chronic myeloid leukemia

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