Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors
<p dir="ltr">Tyrosine kinase inhibitors (TKIs) have remarkably transformed Ph+ chronic myeloid leukemia (CML) management; however, TKI resistance remains a major clinical challenge. Mutations in <i>BCR-ABL1</i> are well studied but fail to explain 20–40% of resistant case...
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2022
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| _version_ | 1864513553286823936 |
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| author | Mohamed A. Ismail (418629) |
| author2 | Gheyath K. Nasrallah (9200525) Maria Monne (4166524) Ali AlSayab (17150992) Mohamed A. Yassin (8361183) Govindarajulu Varadharaj (14778931) Salma Younes (6424865) Claudio Sorio (212799) Richard Cook (70389) Helmout Modjtahedi (532099) Nader I. Al-Dewik (14152884) |
| author2_role | author author author author author author author author author author |
| author_facet | Mohamed A. Ismail (418629) Gheyath K. Nasrallah (9200525) Maria Monne (4166524) Ali AlSayab (17150992) Mohamed A. Yassin (8361183) Govindarajulu Varadharaj (14778931) Salma Younes (6424865) Claudio Sorio (212799) Richard Cook (70389) Helmout Modjtahedi (532099) Nader I. Al-Dewik (14152884) |
| author_role | author |
| dc.creator.none.fl_str_mv | Mohamed A. Ismail (418629) Gheyath K. Nasrallah (9200525) Maria Monne (4166524) Ali AlSayab (17150992) Mohamed A. Yassin (8361183) Govindarajulu Varadharaj (14778931) Salma Younes (6424865) Claudio Sorio (212799) Richard Cook (70389) Helmout Modjtahedi (532099) Nader I. Al-Dewik (14152884) |
| dc.date.none.fl_str_mv | 2022-03-01T00:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1016/j.gene.2021.146101 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Description_of_PTPRG_genetic_variants_identified_in_a_cohort_of_Chronic_Myeloid_Leukemia_patients_and_their_ability_to_influence_response_to_Tyrosine_kinase_Inhibitors/24314257 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Cardiovascular medicine and haematology Clinical sciences Chronic Myeloid Leukemia Protein Tyrosine Phosphatase Receptor Type G BCR-ABL1 Single Nucleotide Polymorphisms Tyrosine Kinase Inhibitors Therapeutic Modalities |
| dc.title.none.fl_str_mv | Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Tyrosine kinase inhibitors (TKIs) have remarkably transformed Ph+ chronic myeloid leukemia (CML) management; however, TKI resistance remains a major clinical challenge. Mutations in <i>BCR-ABL1</i> are well studied but fail to explain 20–40% of resistant cases, suggesting the activation of alternative, <i>BCR-ABL1</i>-independent pathways. Protein Tyrosine Phosphatase Receptor Gamma (<i>PTPRG</i>), a tumor suppressor, was found to be well expressed in CML patients responsive to TKIs and remained at low level in resistant patients. In this study, we aimed to identify genetic variants in <i>PTPRG</i> that could potentially modulate TKIs response in CML patients. DNA was extracted from peripheral blood samples collected from two CML cohorts (Qatar and Italy) and targeted exome sequencing was performed. Among 31 CML patients, six were TKI-responders and 25 were TKI-non-responsive. Sequencing identified ten variants, seven were annotated and three were novel SNPs (c.1602_1603insC, c.85+14412delC, and c.2289-129delA). Among them, five variants were identified in 15 resistant cases. Of these, one novel exon variant (c.1602_1603insC), c.841-29C>T (rs199917960) and c.1378-224A>G (rs2063204) were found to be significantly different between the resistant cases compared to responders. Our findings suggest that <i>PTPRG</i> variants may act as an indirect resistance mechanism of <i>BCR-ABL1</i> to affect TKI treatment.</p><h2>Other Information</h2><p dir="ltr">Published in: Gene<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.gene.2021.146101" target="_blank">https://dx.doi.org/10.1016/j.gene.2021.146101</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_0eca597a87e3f6b55c3d1f9eb584cbc0 |
| identifier_str_mv | 10.1016/j.gene.2021.146101 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/24314257 |
| publishDate | 2022 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase InhibitorsMohamed A. Ismail (418629)Gheyath K. Nasrallah (9200525)Maria Monne (4166524)Ali AlSayab (17150992)Mohamed A. Yassin (8361183)Govindarajulu Varadharaj (14778931)Salma Younes (6424865)Claudio Sorio (212799)Richard Cook (70389)Helmout Modjtahedi (532099)Nader I. Al-Dewik (14152884)Biological sciencesGeneticsBiomedical and clinical sciencesCardiovascular medicine and haematologyClinical sciencesChronic Myeloid LeukemiaProtein Tyrosine Phosphatase Receptor Type GBCR-ABL1Single Nucleotide PolymorphismsTyrosine Kinase InhibitorsTherapeutic Modalities<p dir="ltr">Tyrosine kinase inhibitors (TKIs) have remarkably transformed Ph+ chronic myeloid leukemia (CML) management; however, TKI resistance remains a major clinical challenge. Mutations in <i>BCR-ABL1</i> are well studied but fail to explain 20–40% of resistant cases, suggesting the activation of alternative, <i>BCR-ABL1</i>-independent pathways. Protein Tyrosine Phosphatase Receptor Gamma (<i>PTPRG</i>), a tumor suppressor, was found to be well expressed in CML patients responsive to TKIs and remained at low level in resistant patients. In this study, we aimed to identify genetic variants in <i>PTPRG</i> that could potentially modulate TKIs response in CML patients. DNA was extracted from peripheral blood samples collected from two CML cohorts (Qatar and Italy) and targeted exome sequencing was performed. Among 31 CML patients, six were TKI-responders and 25 were TKI-non-responsive. Sequencing identified ten variants, seven were annotated and three were novel SNPs (c.1602_1603insC, c.85+14412delC, and c.2289-129delA). Among them, five variants were identified in 15 resistant cases. Of these, one novel exon variant (c.1602_1603insC), c.841-29C>T (rs199917960) and c.1378-224A>G (rs2063204) were found to be significantly different between the resistant cases compared to responders. Our findings suggest that <i>PTPRG</i> variants may act as an indirect resistance mechanism of <i>BCR-ABL1</i> to affect TKI treatment.</p><h2>Other Information</h2><p dir="ltr">Published in: Gene<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.gene.2021.146101" target="_blank">https://dx.doi.org/10.1016/j.gene.2021.146101</a></p>2022-03-01T00:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1016/j.gene.2021.146101https://figshare.com/articles/journal_contribution/Description_of_PTPRG_genetic_variants_identified_in_a_cohort_of_Chronic_Myeloid_Leukemia_patients_and_their_ability_to_influence_response_to_Tyrosine_kinase_Inhibitors/24314257CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/243142572022-03-01T00:00:00Z |
| spellingShingle | Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors Mohamed A. Ismail (418629) Biological sciences Genetics Biomedical and clinical sciences Cardiovascular medicine and haematology Clinical sciences Chronic Myeloid Leukemia Protein Tyrosine Phosphatase Receptor Type G BCR-ABL1 Single Nucleotide Polymorphisms Tyrosine Kinase Inhibitors Therapeutic Modalities |
| status_str | publishedVersion |
| title | Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors |
| title_full | Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors |
| title_fullStr | Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors |
| title_full_unstemmed | Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors |
| title_short | Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors |
| title_sort | Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors |
| topic | Biological sciences Genetics Biomedical and clinical sciences Cardiovascular medicine and haematology Clinical sciences Chronic Myeloid Leukemia Protein Tyrosine Phosphatase Receptor Type G BCR-ABL1 Single Nucleotide Polymorphisms Tyrosine Kinase Inhibitors Therapeutic Modalities |