Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia

Järås, Marcus; Miller, Peter G.; Chu, Lisa P.; Puram, Rishi V.; Fink, Emma C.; Schneider, Rebekka K.; Al‐Shahrour, Fátima; Peña, Pablo; Breyfogle, Lawrence J.; Hartwell, Kimberly A.; McConkey, Marie; Cowley, Glenn S.; Root, David E.; Kharas, Michael G.; Mullally, Ann; Ebert, Benjamin L.

doi:10.1084/jem.20131033

Cited by 80 publications

(75 citation statements)

References 28 publications

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“…CK1α has previously been implicated in Wnt-β-catenin signaling in cancer (Cruciat, 2014), but this does not appear to be the operant mechanism of action in our system given that there is no evidence for nuclear β-catenin in the xenograft tumors by IHC and no evidence for upregulation of a β-catenin signature by RNASeq/GSEA. Recent studies suggest CK1α as a potential therapeutic target in acute myeloid leukemia (Järås et al, 2014), 5q-myelodysplastic syndrome (Schneider et al, 2014), and multiple myeloma (Hu et al, 2015), and our current studies would suggest NEK6/CK1α signaling as a possible therapeutic target in certain forms of castration-resistant prostate cancer. However, given that the substrates identified here are not sufficient to confer castration resistance, there are likely other substrates important to the phenotype that we have yet to characterize (including, for example, the other 6 putative substrates identified in the in vitro phosphoproteomic screen).…”

Section: Resultsmentioning

confidence: 56%

Molecular Determinants of Hormone-Refractory Prostate Cancer

Choudhury¹

2015

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERDana-Farber Cancer Institute 450 Brookline Ave Boston, MA 02215 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTWe have performed a high throughput, in vivo genetic screen to identify kinases that permit androgen-dependent transformed prostate epithelial cells (LHSR-AR cells) to form tumors in female animals. In addition to known prostate cancer oncogenes and mediators of androgen independence (mutated KRAS, constitutively active MEK, RAF1, ERBB2, AKT1, PIM1 and PIM2), overexpression of the Never In Mitosis A (NIMA) related kinase 6 (NEK6) reproducibly yielded androgen-independent tumors. NEK6 is overexpressed in prostate cancer cell lines compared to their normal counterparts and is overexpressed in a subset of human prostate cancers. Expression of NEK6 confers castration resistance to established tumors in male mice, and suppressing NEK6 expression restores sensitivity to castration. Castration-resistant tumors generated through NEK6 overexpression are predominantly squamous in histology and do not express androgen receptor (AR), and NEK6 does not activate AR signaling. Phosphoproteome and interactome analysis reveals the transcription factors FOXJ2 and NCOA5, as well as the kinases CK1α and YES1 to be novel substrates. The gene expression profile mediated by NEK6 overexpression in tumors from castrated mice demonstrates elements of both differentiation and immune signaling, and phosphomimic forms of FOXJ2, YES1, and CK1α (but not NCOA5) recapitulate elements of this signature, particularly CK1α with markers of squamous differentiation. These studies reveal a novel mechanism of resistance in androgen pathway independent prostate cancer (APIPC). SUBJECT TERMSProstate cancer, hormone refractory, castration resistant, androgen independent, NEK6

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Section: Resultsmentioning

confidence: 56%

Molecular Determinants of Hormone-Refractory Prostate Cancer

Choudhury¹

2015

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“…25 The Trp53 2/2 c-Kit 1 AML cells express TLR1 (supplemental Figure 9A), and similar to Trp53 1/1 MLL-AF9 leukemia cells, they could be forced into apoptosis (supplemental Figure 9B), and differentiation (supplemental Figure 9C), on TLR1/TLR2 activation. These findings demonstrate that activation of TLR1/TLR2 induces apoptosis and differentiation of AML cells in a p53-independent manner.…”

Section: Aml1-eto9a Aml Cellsmentioning

confidence: 95%

“…Mouse MLL-AF9 leukemias in a C57BL/6 dsRed transgenic background (6051; The Jackson Laboratory, Bar Harbor, ME), and Trp53 2/2 background (002101; The Jackson Laboratory), were previously generated by retroviral expression of MLL-AF9 in murine hematopoietic stem and progenitor cells (HSPCs). 24,25 Similarly, mouse AML1-ETO9a leukemias were previously generated by retroviral expression of AML1-ETO9a along with EGFP in HSPCs. 26,27 Leukemia cells were propagated by transplantation into sublethally irradiated (600 cGy) C57BL/6 mice recipients.…”

Section: Murine Leukemia Modelsmentioning

confidence: 99%

“…To this end, we used a murine AML model driven by the MLL-AF9 fusion gene in a dsRed-transgenic background, previously used to reveal novel biology of LSCs. 24,25,37,38 Serial transplantations result in reproducible engraftment of leukemia cells in BM and spleens of recipient mice. 24 We found TLR1 to be expressed on leukemic granulocyte and macrophage progenitor cells, enriched for LSCs in this model (supplemental Figure 5A).…”

Section: Tlr1/tlr2 Activation Suppresses Leukemia-initiating Cellsmentioning

confidence: 99%

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Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells

Eriksson¹,

Peña-Martínez²,

Ramakrishnan³

et al. 2017

Blood Advances

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Key Points• TLR1 is upregulated on primitive AML cells.• Agonistic targeting of TLR1/TLR2 induces apoptosis and differentiation of primitive AML cells in vivo.Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities.Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary MLL-AF9 AML cells, we demonstrate that p53 is dispensable for Pam3CSK4-induced apoptosis and differentiation. Moreover, murine AML1-ETO9a-driven AML cells also were forced into apoptosis and differentiation on TLR1/TLR2 activation, demonstrating that the antileukemic effects observed were not confined to MLL-rearranged AML.We further evaluated whether Pam3CSK4 would exhibit selective antileukemic effects.

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“…Lenalidomide treatment leads to increased ubiquitination of CSNK1A1 and decreased protein abundance ( Figure 3). CSNK1A1 was shown as a therapeutic target in a murine model of AML [80,81] and in MDS with del(5q) [82,83]. CSNK1A1 negatively regulates β-catenin which drives stem cell self-renewal and CSNK1A1 haploinsufficiency causes the initial clonal expansion in patients with the del(5q) MDS and contributes to the pathogenesis of del(5q) MDS.…”

Section: An Alternative Crl4mentioning

confidence: 99%

Immunomodulatory drugs and their therapeutic effect in hematological malignancies through cereblon

Fuchs¹

2017

Hematol Med Oncol

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Immunomodulatory drugs (IMiDs), today also known as cereblon (CRBN) binding drugs, are therapeutically important anti-cancer and anti-inflammatory drugs. IMiDs are analogs of their prototype compound thalidomide. IMiDs have immune-modulation, anti-angiogenic, anti-inflammatory and anti-proliferative effects. CRBN is a component and substrate receptor of the Cullin 4 Ring E3 Ubiquitin Protein Ligase complex (CRL4). CRL4 consists of Cullin 4, RING finger protein (Roc1), and DNA damage binding protein 1 (DDB1). CRBN binds to its substrate proteins and it leads to ubiquitination of these substrates by the CRL4. CRBN is also involved in IMiDs-mediated T-cell co-stimulation and cytokine production. CRBN is a primary target of thalidomide teratogenicity. The binding of IMiDs to CRBN is associated with cytotoxicity of IMiDs and is used to treat multiple myeloma (MM), myelodysplastic syndromes (MDS), lymphomas and chronic lymphocytic leukemia. CRBN is composed of an N-terminal ATP-dependent serine protease Lon-like domain, which links to the E3 ubiquitin protein ligase complex CRL4, and a C-terminal domain, which binds IMiDs. CRBN binding is mediated by a glutarimide ring in thalidomide, lenalidomide, pomalidomide, CC-122, CC-220, CC-885 and CC-90009. Development of effector molecules mediating targeted ubiquitination of disease related proteins through cereblon is a new important way in pharmacology.

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Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia

Abstract: Targeting Csnk1a1 provides a potential therapeutic approach for AML associated with nonmutated Tp53.

Cited by 80 publications

References 28 publications

Molecular Determinants of Hormone-Refractory Prostate Cancer

Molecular Determinants of Hormone-Refractory Prostate Cancer

Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells

Immunomodulatory drugs and their therapeutic effect in hematological malignancies through cereblon

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