CBL mutations in chronic myelomonocytic leukemia often occur in the RING domain with multiple subclones per patient: Implications for targeting.
Chronic myelomonocytic leukemia (CMML) is a rare blood cancer of older adults (3 in every 1,000,000 persons) characterized by poor survival and lacking effective mutation-specific therapy. Mutations in the ubiquitin ligase Cbl occur frequently in CMML and share biological and molecular features with...
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Public Library of Science (PLoS)
2024-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0310641 |
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| author | Kelly Lim Winnie L Kan Pramod C Nair Monika Kutyna Angel F Lopez Timothy Hercus David M Ross Steven Lane Chun Yew Fong Anna Brown Agnes Yong David Yeung Timothy Hughes Devendra Hiwase Daniel Thomas |
| author_facet | Kelly Lim Winnie L Kan Pramod C Nair Monika Kutyna Angel F Lopez Timothy Hercus David M Ross Steven Lane Chun Yew Fong Anna Brown Agnes Yong David Yeung Timothy Hughes Devendra Hiwase Daniel Thomas |
| author_sort | Kelly Lim |
| collection | DOAJ |
| description | Chronic myelomonocytic leukemia (CMML) is a rare blood cancer of older adults (3 in every 1,000,000 persons) characterized by poor survival and lacking effective mutation-specific therapy. Mutations in the ubiquitin ligase Cbl occur frequently in CMML and share biological and molecular features with a clonal disease occurring in children, juvenile myelomonocytic leukemia (JMML). Here we analyzed the clinical presentations, molecular features and immunophenotype of CMML patients with CBL mutations enrolled in a prospective Phase II clinical trial stratified according to molecular markers. Clinically, CBL mutations were associated with increased bone marrow blasts at diagnosis, leukocytosis and splenomegaly, similar to patients harboring NRAS or KRAS mutations. Interestingly, 64% of patients presented with more than one CBL variant implying a complex subclonal architecture, often with co-occurrence of TET2 mutations. We found CBL mutations in CMML frequently clustered in the RING domain in contrast to JMML, where mutations frequently involve the linker helix region (P<0.0001). According to our comparative alignment of available X-ray structures, mutations in the linker helix region such as Y371E give rise to conformational differences that could be exploited by targeted therapy approaches. Furthermore, we noted an increased percentage of CMML CD34+ stem and progenitor cells expressing CD116 and CD131 in all CBL mutant cases and increased CD116 receptor density compared to healthy controls, similar to CMML overall. In summary, our data demonstrate that CBL mutations are associated with distinct molecular and clinical features in CMML and are potentially targetable with CD116-directed immunotherapy. |
| format | Article |
| id | doaj-art-d0c56bfbdfa040e896812cd439a6ecdf |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-d0c56bfbdfa040e896812cd439a6ecdf2025-01-26T05:31:21ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-01199e031064110.1371/journal.pone.0310641CBL mutations in chronic myelomonocytic leukemia often occur in the RING domain with multiple subclones per patient: Implications for targeting.Kelly LimWinnie L KanPramod C NairMonika KutynaAngel F LopezTimothy HercusDavid M RossSteven LaneChun Yew FongAnna BrownAgnes YongDavid YeungTimothy HughesDevendra HiwaseDaniel ThomasChronic myelomonocytic leukemia (CMML) is a rare blood cancer of older adults (3 in every 1,000,000 persons) characterized by poor survival and lacking effective mutation-specific therapy. Mutations in the ubiquitin ligase Cbl occur frequently in CMML and share biological and molecular features with a clonal disease occurring in children, juvenile myelomonocytic leukemia (JMML). Here we analyzed the clinical presentations, molecular features and immunophenotype of CMML patients with CBL mutations enrolled in a prospective Phase II clinical trial stratified according to molecular markers. Clinically, CBL mutations were associated with increased bone marrow blasts at diagnosis, leukocytosis and splenomegaly, similar to patients harboring NRAS or KRAS mutations. Interestingly, 64% of patients presented with more than one CBL variant implying a complex subclonal architecture, often with co-occurrence of TET2 mutations. We found CBL mutations in CMML frequently clustered in the RING domain in contrast to JMML, where mutations frequently involve the linker helix region (P<0.0001). According to our comparative alignment of available X-ray structures, mutations in the linker helix region such as Y371E give rise to conformational differences that could be exploited by targeted therapy approaches. Furthermore, we noted an increased percentage of CMML CD34+ stem and progenitor cells expressing CD116 and CD131 in all CBL mutant cases and increased CD116 receptor density compared to healthy controls, similar to CMML overall. In summary, our data demonstrate that CBL mutations are associated with distinct molecular and clinical features in CMML and are potentially targetable with CD116-directed immunotherapy.https://doi.org/10.1371/journal.pone.0310641 |
| spellingShingle | Kelly Lim Winnie L Kan Pramod C Nair Monika Kutyna Angel F Lopez Timothy Hercus David M Ross Steven Lane Chun Yew Fong Anna Brown Agnes Yong David Yeung Timothy Hughes Devendra Hiwase Daniel Thomas CBL mutations in chronic myelomonocytic leukemia often occur in the RING domain with multiple subclones per patient: Implications for targeting. PLoS ONE |
| title | CBL mutations in chronic myelomonocytic leukemia often occur in the RING domain with multiple subclones per patient: Implications for targeting. |
| title_full | CBL mutations in chronic myelomonocytic leukemia often occur in the RING domain with multiple subclones per patient: Implications for targeting. |
| title_fullStr | CBL mutations in chronic myelomonocytic leukemia often occur in the RING domain with multiple subclones per patient: Implications for targeting. |
| title_full_unstemmed | CBL mutations in chronic myelomonocytic leukemia often occur in the RING domain with multiple subclones per patient: Implications for targeting. |
| title_short | CBL mutations in chronic myelomonocytic leukemia often occur in the RING domain with multiple subclones per patient: Implications for targeting. |
| title_sort | cbl mutations in chronic myelomonocytic leukemia often occur in the ring domain with multiple subclones per patient implications for targeting |
| url | https://doi.org/10.1371/journal.pone.0310641 |
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