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Article ; Online: High expression level of ROR1 and ROR1-signaling associates with venetoclax resistance in chronic lymphocytic leukemia.

Ghia, Emanuela M / Rassenti, Laura Z / Choi, Michael Y / Quijada-Álamo, Miguel / Chu, Elvin / Widhopf, George F / Kipps, Thomas J

Leukemia

2022 Volume 36, Issue 6, Page(s) 1609–1618

Abstract: Although the BH3-mimetic venetoclax is highly cytotoxic for chronic lymphocytic leukemia (CLL) cells, some patients with CLL fail to clear minimal residual disease (MRD). We examined the CLL cells of seven such patients (CLL1-7) and found each had high- ... ...

Abstract	Although the BH3-mimetic venetoclax is highly cytotoxic for chronic lymphocytic leukemia (CLL) cells, some patients with CLL fail to clear minimal residual disease (MRD). We examined the CLL cells of seven such patients (CLL1-7) and found each had high-level expression of ROR1. By examining the CLL cells from such patients prior to therapy at SC1 and then more than 1 year later (Sample Collection 2 (SC2)), when they had progressive increases in MRD despite continued venetoclax therapy, we found the levels of ROR1 expressed on CLL cells at SC2 were significantly higher than that on CLL cells collected at SC1. At SC2, we also observed upregulation of genes induced by Wnt5a-induced ROR1 signaling, including BCL2L1. Transduction of the CLL-cell-line MEC1 to express ROR1 enhanced expression of target genes induced by ROR1-signaling, increased expression of BCL-XL, and enhanced resistance to venetoclax, even in MEC1 made to express mutant forms of BCL2, which are associated with venetoclax resistance. Treatment of primary CLL cells with Wnt5a also increased their resistance to venetoclax, an effect that could be inhibited by the anti-ROR1 mAb (UC-961, zilovertamab). Collectively, these studies indicate that Wnt5a-induced ROR1-signaling can enhance resistance to venetoclax therapy.
MeSH term(s)	Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Receptor Tyrosine Kinase-like Orphan Receptors/genetics ; Receptor Tyrosine Kinase-like Orphan Receptors/metabolism ; Sulfonamides/pharmacology
Chemical Substances	Bridged Bicyclo Compounds, Heterocyclic ; Sulfonamides ; ROR1 protein, human (EC 2.7.10.1) ; Receptor Tyrosine Kinase-like Orphan Receptors (EC 2.7.10.1) ; venetoclax (N54AIC43PW)
Language	English
Publishing date	2022-04-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-022-01543-y
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Article ; Online: A phase 1b study of zilovertamab in combination with paclitaxel for locally advanced/unresectable or metastatic Her2-negative breast cancer.

Shatsky, Rebecca A / Batra-Sharma, Hemali / Helsten, Teresa / Schwab, Richard B / Pittman, Emily I / Pu, Minya / Weihe, Elizabeth / Ghia, Emanuela M / Rassenti, Laura Z / Molinolo, Alfredo / Cabrera, Betty / Breitmeyer, James B / Widhopf, George F / Messer, Karen / Jamieson, Catriona / Kipps, Thomas J / Parker, Barbara A

Breast cancer research : BCR

2024 Volume 26, Issue 1, Page(s) 32

Abstract: Background: Zilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that zilovertamab was well tolerated ... ...

Abstract	Background: Zilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that zilovertamab was well tolerated and effective in inhibiting ROR1-signaling, which leads to activation of ERK1/2, NF-κB, and NRF2 target genes. This phase 1b study evaluated the safety and tolerability of zilovertamab with paclitaxel in patients with advanced breast cancer. Patients and methods: Eligible patients had locally advanced, unresectable, or metastatic HER2 Results: Study patients had received a median of 4 prior therapies (endocrine therapy + chemotherapy) for locally advanced, unresectable, or metastatic disease. No patient discontinued therapy due to toxicity ascribed to zilovertamab. Adverse events were consistent with the known safety profile of paclitaxel. Of 16 patients, 6 (38%) had a partial response, and 6/16 (38%) patients had stable disease as best tumor response. Conclusion: The combination of zilovertamab and paclitaxel was safe and well tolerated in heavily pre-treated advanced breast cancer patients. Further evaluation of ROR1 targeting in breast cancer patients with zilovertamab is warranted. Trial registration: NCT02776917. Registered on ClinicalTrials.gov on 05/17/2016.
MeSH term(s)	Humans ; Female ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Paclitaxel/therapeutic use ; Receptor, ErbB-2/genetics ; Antibodies, Monoclonal, Humanized ; Antineoplastic Combined Chemotherapy Protocols/adverse effects
Chemical Substances	Paclitaxel (P88XT4IS4D) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Antibodies, Monoclonal, Humanized
Language	English
Publishing date	2024-02-26
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/s13058-024-01782-0
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Zs.A 5494: Show issues

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Article ; Online: Wnt5a enhances proliferation of chronic lymphocytic leukemia and ERK1/2 phosphorylation via a ROR1/DOCK2-dependent mechanism.

Hasan, Md Kamrul / Ghia, Emanuela M / Rassenti, Laura Z / Widhopf, George F / Kipps, Thomas J

Leukemia

2020 Volume 35, Issue 6, Page(s) 1621–1630

Abstract: Patients with chronic lymphocytic leukemia (CLL) have high plasma-levels of Wnt5a, which can induce phosphorylation of ERK1/2 and enhance CLL-cell proliferation. Such effects could be inhibited by treatment with an ERK1/2 inhibitor, ERK1/2-specific siRNA, ...

Abstract	Patients with chronic lymphocytic leukemia (CLL) have high plasma-levels of Wnt5a, which can induce phosphorylation of ERK1/2 and enhance CLL-cell proliferation. Such effects could be inhibited by treatment with an ERK1/2 inhibitor, ERK1/2-specific siRNA, or cirmtuzumab, an anti-ROR1 mAb. The CLL-derived line, MEC1, expresses Wnt5a, but not ROR1. MEC1 cells transfected to express ROR1 (MEC1-ROR1) had higher levels of phosphorylated ERK1/2 than parental MEC1, or MEC1 transfected with ROR1ΔPRD, a truncated ROR1 lacking the cytoplasmic proline-rich domain (PRD), or ROR1
MeSH term(s)	Apoptosis ; Cell Proliferation ; GTPase-Activating Proteins/genetics ; GTPase-Activating Proteins/metabolism ; Gene Expression Regulation, Neoplastic ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/metabolism ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Mitogen-Activated Protein Kinase 1/genetics ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/genetics ; Mitogen-Activated Protein Kinase 3/metabolism ; Receptor Tyrosine Kinase-like Orphan Receptors/genetics ; Receptor Tyrosine Kinase-like Orphan Receptors/metabolism ; Tumor Cells, Cultured ; Wnt-5a Protein/genetics ; Wnt-5a Protein/metabolism
Chemical Substances	DOCK2 protein, human ; GTPase-Activating Proteins ; Guanine Nucleotide Exchange Factors ; WNT5A protein, human ; Wnt-5a Protein ; ROR1 protein, human (EC 2.7.10.1) ; Receptor Tyrosine Kinase-like Orphan Receptors (EC 2.7.10.1) ; MAPK1 protein, human (EC 2.7.11.24) ; MAPK3 protein, human (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24)
Language	English
Publishing date	2020-10-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-020-01055-7
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Article ; Online: Wnt5a causes ROR1 to complex and activate cortactin to enhance migration of chronic lymphocytic leukemia cells.

Hasan, Md Kamrul / Rassenti, Laura / Widhopf, George F / Yu, Jian / Kipps, Thomas J

Leukemia

2018 Volume 33, Issue 3, Page(s) 653–661

Abstract: Chronic lymphocytic leukemia cells (CLL) migrate between the blood and lymphoid tissues in response to chemokines. Such migration requires structured cytoskeletal-actin polymerization, which may involve the protein cortactin. We discovered that treatment ...

Abstract	Chronic lymphocytic leukemia cells (CLL) migrate between the blood and lymphoid tissues in response to chemokines. Such migration requires structured cytoskeletal-actin polymerization, which may involve the protein cortactin. We discovered that treatment of CLL cells with Wnt5a causes Receptor tyosin kinase-like orphan receptor 1 (ROR1) to bind cortactin, which undergoes tyrosine phosphorylation at Y421, recruits ARHGEF1, and activates RhoA, thereby enhancing leukemia-cell migration; such effects could be inhibited by cirmtuzumab, a humanized mAb specific for ROR1. We transfected the CLL-cell-line MEC1 with either full-length ROR1 or various mutant forms of ROR1 to examine the structural features required for binding cortactin. We found that the proline-rich domain (PRD) was necessary for ROR1 to recruit cortactin. We generated MEC1 cells that each expressed a mutant form of ROR1 with a single amino-acid substitution of alanine (A) for proline (P) in potential SH3-binding sites in the ROR1-PRD at positions 784, 808, 826, 841, or 850. In contrast to wild-type ROR1, or other ROR1
MeSH term(s)	Actins/metabolism ; Alanine/metabolism ; Amino Acid Substitution/drug effects ; Antibodies, Monoclonal/pharmacology ; Binding Sites/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Movement/physiology ; Cortactin/metabolism ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Phosphorylation/drug effects ; Receptor Tyrosine Kinase-like Orphan Receptors/metabolism ; Rho Guanine Nucleotide Exchange Factors/metabolism ; Tyrosine/metabolism ; Wnt-5a Protein/metabolism ; rhoA GTP-Binding Protein/metabolism
Chemical Substances	Actins ; Antibodies, Monoclonal ; CTTN protein, human ; Cortactin ; Rho Guanine Nucleotide Exchange Factors ; WNT5A protein, human ; Wnt-5a Protein ; Tyrosine (42HK56048U) ; ROR1 protein, human (EC 2.7.10.1) ; Receptor Tyrosine Kinase-like Orphan Receptors (EC 2.7.10.1) ; rhoA GTP-Binding Protein (EC 3.6.5.2) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2018-12-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-018-0306-7
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Zs.A 2295: Show issues

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Article: Wnt5a induces ROR1 to recruit cortactin to promote breast-cancer migration and metastasis.

Hasan, Md Kamrul / Widhopf, George F / Zhang, Suping / Lam, Sharon M / Shen, Zhouxin / Briggs, Steven P / Parker, Barbara A / Kipps, Thomas J

NPJ breast cancer

2019 Volume 5, Page(s) 35

Abstract: ROR1 is a conserved oncoembryonic surface protein expressed in breast cancer. Here we report that ROR1 associates with cortactin in primary breast-cancer cells or in MCF7 transfected to express ROR1. Wnt5a also induced ROR1-dependent tyrosine ... ...

Abstract	ROR1 is a conserved oncoembryonic surface protein expressed in breast cancer. Here we report that ROR1 associates with cortactin in primary breast-cancer cells or in MCF7 transfected to express ROR1. Wnt5a also induced ROR1-dependent tyrosine phosphorylation of cortactin (Y421), which recruited ARHGEF1 to activate RhoA and promote breast-cancer-cell migration; such effects could be inhibited by cirmtuzumab, a humanized mAb specific for ROR1. Furthermore, treatment of mice bearing breast-cancer xenograft with cirmtuzumab inhibited cortactin phosphorylation in vivo and impaired metastatic development. We established that the proline at 841 of ROR1 was required for it to recruit cortactin and ARHGEF1, activate RhoA, and enhance breast-cancer-cell migration in vitro or development of metastases in vivo. Collectively, these studies demonstrate that the interaction of ROR1 with cortactin plays an important role in breast-cancer-cell migration and metastasis.
Language	English
Publishing date	2019-10-25
Publishing country	United States
Document type	Journal Article
ISSN	2374-4677
ISSN	2374-4677
DOI	10.1038/s41523-019-0131-9
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Article ; Online: Cirmtuzumab inhibits ibrutinib-resistant, Wnt5a-induced Rac1 activation and proliferation in mantle cell lymphoma.

Yu, Jian / Chen, Yun / Chen, Liguang / Zhang, Ling / Rassenti, Laura Z / Widhopf, George F / Kipps, Thomas J

Oncotarget

2018 Volume 9, Issue 37, Page(s) 24731–24736

Abstract: Cirmtuzumab may enhance the therapeutic activity of ibrutinib by inhibiting ROR1-dependent signaling pathway in patients with chronic lymphocytic leukemia (CLL). Mantle cell lymphoma (MCL) is B-cell malignancy that also expresses ROR1. In this study, we ... ...

Abstract	Cirmtuzumab may enhance the therapeutic activity of ibrutinib by inhibiting ROR1-dependent signaling pathway in patients with chronic lymphocytic leukemia (CLL). Mantle cell lymphoma (MCL) is B-cell malignancy that also expresses ROR1. In this study, we found that the plasma of patients with MCL had high levels of Wnt5a, a ROR1 ligand, that were comparable to those found in patients with CLL; in contrast Wnt5a was virtually undetectable in the plasma of age-matched healthy adults. We also found that Wnt5a induced Rac1 activation in the primary MCL cells. Cirmtuzumab, but not ibrutinib, could inhibit the capacity of Wnt5a to induce primary MCL cells to activate Rac1. Addition of exogenous Wnt5a
Language	English
Publishing date	2018-05-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.25340
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Article ; Online: Cirmtuzumab blocks Wnt5a/ROR1 stimulation of NF-κB to repress autocrine STAT3 activation in chronic lymphocytic leukemia.

Chen, Yun / Chen, Liguang / Yu, Jian / Ghia, Emanuela M / Choi, Michael Y / Zhang, Ling / Zhang, Suping / Sanchez-Lopez, Elsa / Widhopf, George F / Messer, Karen / Rassenti, Laura Z / Jamieson, Catriona / Kipps, Thomas J

Blood

2019 Volume 134, Issue 13, Page(s) 1084–1094

Abstract: Coculture of nurse-like cells (NLCs) with chronic lymphocytic leukemia (CLL) cells induced leukemia cell phosphorylation of STAT3 (pSTAT3), which could be blocked by anti-Wnt5a antibodies or the anti-ROR1 monoclonal antibody, cirmtuzumab. Time-course ... ...

Abstract	Coculture of nurse-like cells (NLCs) with chronic lymphocytic leukemia (CLL) cells induced leukemia cell phosphorylation of STAT3 (pSTAT3), which could be blocked by anti-Wnt5a antibodies or the anti-ROR1 monoclonal antibody, cirmtuzumab. Time-course studies revealed Wnt5a could induce activation of NF-κB within 30 minutes, but required more than 3 hours to induce pSTAT3. Culture of isolated CLL cells for 24 hours revealed Wnt5a-induced expression of interleukin 6 (IL-6), IL-8, CCL2, CCL3, CCL4, and CXCL1, which in turn could induce pSTAT3 in unstimulated CLL cells within 30 minutes. We found that Wnt5a could induce CLL cell expression of NF-κB target genes, including IL-6, and that this effect could be blocked by cirmtuzumab or drugs that inhibit NF-κB. Examination of CLL cells and plasma collected from patients treated with cirmtuzumab revealed reduced levels of phosphorylated p65 and diminished expression of NF-κB and STAT3 target genes in CLL cells, as well as lower plasma levels of IL-6, in the samples after therapy. Collectively, these studies indicate that Wnt5a/ROR1-dependent signaling contributes to CLL cell activation of NF-κB, which in turn causes autocrine IL-6-induced activation of pSTAT3. As such, this study demonstrates that cirmtuzumab can inhibit leukemia cell activation of both NF-κB and STAT3 in patients with CLL.
MeSH term(s)	Antibodies, Monoclonal, Humanized/pharmacology ; Antineoplastic Agents, Immunological/pharmacology ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology ; NF-kappa B/immunology ; Receptor Tyrosine Kinase-like Orphan Receptors/immunology ; STAT3 Transcription Factor/immunology ; Tumor Cells, Cultured ; Wnt-5a Protein/immunology
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antineoplastic Agents, Immunological ; NF-kappa B ; STAT3 Transcription Factor ; STAT3 protein, human ; WNT5A protein, human ; Wnt-5a Protein ; ROR1 protein, human (EC 2.7.10.1) ; Receptor Tyrosine Kinase-like Orphan Receptors (EC 2.7.10.1) ; cirmtuzumab (FEH7RQ7B3J)
Language	English
Publishing date	2019-08-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2019001366
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 364: Show issues

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Article ; Online: Analyses of recombinant stereotypic IGHV3-21-encoded antibodies expressed in chronic lymphocytic leukemia.

Ghia, Emanuela M / Widhopf, George F / Rassenti, Laura Z / Kipps, Thomas J

Journal of immunology (Baltimore, Md. : 1950)

2011 Volume 186, Issue 11, Page(s) 6338–6344

Abstract: Chronic lymphocytic leukemia (CLL) cells that use IgH encoded by IGHV3-21 and that have a particular stereotypic third CDR (HCDR3), DANGMDV (motif-1), almost invariably express Ig L chains (IgL) encoded by IGLV3-21, whereas CLL that use IGHV3-21-encoded ... ...

Abstract	Chronic lymphocytic leukemia (CLL) cells that use IgH encoded by IGHV3-21 and that have a particular stereotypic third CDR (HCDR3), DANGMDV (motif-1), almost invariably express Ig L chains (IgL) encoded by IGLV3-21, whereas CLL that use IGHV3-21-encoded IgH with another stereotypic HCDR3, DPSFYSSSWTLFDY (motif-2), invariably express κ-IgL encoded by IGKV3-20. This nonstochastic pairing could reflect steric factors that preclude these IgH from pairing with other IgL or selection for an Ig with a particular Ag-binding activity. We generated rIg with IGHV3-21-encoded IgH with HCDR3 motif-1 or -2 and IgL encoded by IGKV3-20 or IGLV3-21. Each IgH paired equally well with matched or mismatched κ- or λ-IgL to form functional Ig, which we screened for binding to an array of different Ags. Ig with IGLV3-21-encoded λ-IgL could bind with an affinity of ∼ 2 × 10(-6) M to protein L, a cell-wall protein of Peptostreptococcus magnus, independent of the IgH, indicating that protein L is a superantigen for IGLV3-21-encoded λ-IgL. We also detected Ig binding to cofilin, a highly conserved actin-binding protein. However, cofilin binding was independent of native pairing of IgH and IgL and was not specific for Ig with IgH encoded by IGHV3-21. We conclude that steric factors or the binding activity for protein L or cofilin cannot account for the nonstochastic pairing of IgH and IgL observed for the stereotypic Ig made by CLL cells that express IGHV3-21.
MeSH term(s)	Actin Depolymerizing Factors/immunology ; Actin Depolymerizing Factors/metabolism ; Amino Acid Sequence ; Bacterial Proteins/immunology ; Bacterial Proteins/metabolism ; Binding, Competitive ; Blotting, Western ; Flow Cytometry ; Humans ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin Heavy Chains/immunology ; Immunoglobulin Heavy Chains/metabolism ; Immunoglobulin Light Chains/genetics ; Immunoglobulin Light Chains/immunology ; Immunoglobulin Light Chains/metabolism ; Immunoglobulin Variable Region/genetics ; Immunoglobulin Variable Region/immunology ; Immunoglobulin Variable Region/metabolism ; Immunoglobulin kappa-Chains/genetics ; Immunoglobulin kappa-Chains/immunology ; Immunoglobulin kappa-Chains/metabolism ; Kinetics ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Protein Array Analysis ; Protein Binding ; Recombinant Proteins/immunology ; Recombinant Proteins/metabolism
Chemical Substances	Actin Depolymerizing Factors ; Bacterial Proteins ; Ig L-binding protein, Peptostreptococcus ; Immunoglobulin Heavy Chains ; Immunoglobulin Light Chains ; Immunoglobulin Variable Region ; Immunoglobulin kappa-Chains ; Recombinant Proteins
Language	English
Publishing date	2011-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.0902875
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Ud II Zs.37: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 28: Show issues

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Article: Dielectrophoretic recovery of DNA from plasma for the identification of chronic lymphocytic leukemia point mutations.

Manouchehri, Sareh / Ibsen, Stuart / Wright, Jennifer / Rassenti, Laura / Ghia, Emanuela M / Widhopf, George F / Kipps, Thomas J / Heller, Michael J

International journal of hematologic oncology

2016 Volume 5, Issue 1, Page(s) 27–35

Abstract: Aim: Circulating cell free (ccf) DNA contains information about mutations affecting chronic lymphocytic leukemia (CLL). The complexity of isolating DNA from plasma inhibits the development of point-of-care diagnostics. Here, we introduce an ... ...

Abstract	Aim: Circulating cell free (ccf) DNA contains information about mutations affecting chronic lymphocytic leukemia (CLL). The complexity of isolating DNA from plasma inhibits the development of point-of-care diagnostics. Here, we introduce an electrokinetic method that enables rapid recovery of DNA from plasma. Materials & methods: ccf-DNA was isolated from 25 µl of CLL plasma using dielectrophoresis. The DNA was used for PCR amplification, sequencing and analysis. Results: The ccf-DNA collected from plasma of 5 CLL patients revealed identical mutations to those previously identified by extracting DNA from CLL cells from the same patients. Conclusion: Rapid dielectrophoresis isolation of ccf-DNA directly from plasma provides sufficient amounts of DNA to use for identification of point mutations in genes associated with CLL progression.
Language	English
Publishing date	2016-05-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2692801-2
ISSN	2045-1407 ; 2045-1393
ISSN (online)	2045-1407
ISSN	2045-1393
DOI	10.2217/ijh-2015-0009
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Article ; Online: Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia.

Hasan, Md Kamrul / Yu, Jian / Widhopf, George F / Rassenti, Laura Z / Chen, Liguang / Shen, Zhouxin / Briggs, Steven P / Neuberg, Donna S / Kipps, Thomas J

Blood

2018 Volume 132, Issue 2, Page(s) 170–178

Abstract: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic protein expressed on chronic lymphocytic leukemia (CLL) that can serve as a receptor for Wnt5a, which can promote leukemia cell migration, proliferation, and survival. We found ... ...

Abstract	Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic protein expressed on chronic lymphocytic leukemia (CLL) that can serve as a receptor for Wnt5a, which can promote leukemia cell migration, proliferation, and survival. We found Wnt5a could induce ROR1 to complex with DOCK2 (dedicator of cytokinesis 2) and induce activation of Rac1/2; these effects could be blocked by cirmtuzumab, a humanized anti-ROR1 monoclonal antibody. We find that silencing DOCK2 specifically impaired the capacity of Wnt5a to induce activation of Rac1/2 or enhance CLL cell proliferation. We generated truncated forms of ROR1 and found the cytoplasmic proline-rich domain (PRD) of ROR1 was required for Wnt5a to induce ROR1 to complex with DOCK2 and activate Rac1/2 in the CLL cell-line MEC1. We introduced single amino acid substitutions of proline (P) to alanine (A) in the ROR1-PRD at potential binding sites for the Src-homology 3 domain of DOCK2. In contrast to wild-type ROR1, or other ROR1 P→A variants, ROR1
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation ; GTPase-Activating Proteins ; Guanine Nucleotide Exchange Factors/metabolism ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/etiology ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Protein Binding ; RNA, Small Interfering/genetics ; Receptor Tyrosine Kinase-like Orphan Receptors/metabolism ; Wnt-5a Protein/metabolism ; rac GTP-Binding Proteins/metabolism ; rac1 GTP-Binding Protein/metabolism ; RAC2 GTP-Binding Protein
Chemical Substances	DOCK2 protein, human ; GTPase-Activating Proteins ; Guanine Nucleotide Exchange Factors ; RNA, Small Interfering ; WNT5A protein, human ; Wnt-5a Protein ; ROR1 protein, human (EC 2.7.10.1) ; Receptor Tyrosine Kinase-like Orphan Receptors (EC 2.7.10.1) ; rac GTP-Binding Proteins (EC 3.6.5.2) ; rac1 GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2018-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2017-12-819383
Database	MEDical Literature Analysis and Retrieval System OnLINE

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