Efficacy of ruxolitinib in B‐lymphoblastic leukaemia with the PCM1–JAK2 fusion gene

Wouters, Yannick; Nevejan, Louis; Louwagie, A; Devos, Helena; Dewaele, Barbara; Selleslag, Dominik; Michaux, Lucienne

doi:10.1111/bjh.17340

Cited by 9 publications

(3 citation statements)

References 10 publications

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“…Importantly, an undescribed JAK2 fusion partner, NPAT, was detected due to the translocation t(9;11) in one patient. This may be a treatment-relevant finding since JAK2kinase rearranged ALL with fusions of JAK2 to ATF7IP, EBF1, PAX5, SSBP2, RNPC3, GOLGA5, PCM1 and their effective inhibition by treatment with the JAK inhibitor ruxolitinib have been described previously in anecdotal cases [25][26][27][28]. Preclinical data suggested that ruxolitinib may be effective in BCR-ABL1-like ALL [29].…”

Section: Translocations and Fusionsmentioning

confidence: 57%

The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia

Lühmann

Stelter

Wolter

et al. 2021

Cancers

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Acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer occurring in children. ALL is characterized by structural and numeric genomic aberrations that strongly correlate with prognosis and clinical outcome. Usually, a combination of cyto- and molecular genetic methods (karyotyping, array-CGH, FISH, RT-PCR, RNA-Seq) is needed to identify all aberrations relevant for risk stratification. We investigated the feasibility of optical genome mapping (OGM), a DNA-based method, to detect these aberrations in an all-in-one approach. As proof of principle, twelve pediatric ALL samples were analyzed by OGM, and results were validated by comparing OGM data to results obtained from routine diagnostics. All genomic aberrations including translocations (e.g., dic(9;12)), aneuploidies (e.g., high hyperdiploidy) and copy number variations (e.g., IKZF1, PAX5) known from other techniques were also detected by OGM. Moreover, OGM was superior to well-established techniques for resolution of the more complex structure of a translocation t(12;21) and had a higher sensitivity for detection of copy number alterations. Importantly, a new and unknown gene fusion of JAK2 and NPAT due to a translocation t(9;11) was detected. We demonstrate the feasibility of OGM to detect well-established as well as new putative prognostic markers in an all-in-one approach in ALL. We hope that these limited results will be confirmed with testing of more samples in the future.

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Section: Translocations and Fusionsmentioning

confidence: 57%

The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia

Lühmann

Stelter

Wolter

et al. 2021

Cancers

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“…PCM1 also has been recognized as a key regulator of multiple malignancies. For example, PCM1 was shown to be involved in chromosomal mutations and was associated with glioblastoma and multiple hematological malignancies [32,33]. A complex formed by the combination of PCM1 and canonical autophagy protein GABAPAP was involved in regulating apoptosis and autophagy [34].…”

Section: Discussionmentioning

confidence: 99%

NKD1 targeting PCM1 regulates the therapeutic effects of homoharringtonine on colorectal cancer

et al. 2023

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Background: Colorectal cancer (CRC) is the most common primary malignancy. Homoharringtonine (HHT) has potential therapeutic effects on solid tumors. However, the regulatory target and mechanism of HHT in CRC progression remain elusive.Methods: CCK-8, Edu staining, ow cytometry and Western blotting assay to detect the effect of HHT on proliferation and apoptosis of CRC cells. Transcriptome sequencing screened the drug delivery target of HHT. In vitro rescue experiment and in vivo tumorigenesis experiment detect the targeted interaction between HHT and NKD1. Quantitative proteomics combined with CO-IP and IF experiments to verify the targeted interaction between NKD1 and PCM1.Results: HHT suppressed CRC cells proliferation by inducing cell cycle arrest and apoptosis in vitro and vivo. HHT inhibited NKD1 expression in a concentration and time dependent manner. NKD1 was overexpressed in CRC and its depletion enhanced the therapeutic sensitivity of HHT on CRC, which indicating that NKD1 plays an important role in the development of CRC as the drug delivery target of HHT. Furthermore, proteomic analysis revealed that PCM1 participated the process of NKD1-regulated cell proliferation and cell cycle. NKD1 interacted with PCM1 and promotes PCM1 degradation through the ubiquitin-proteasome pathway. The overexpression of PCM1 effectively reversed the inhibition of siNKD1 on cell cycle.Conclusions: These results suggested that NKD1 targeting PCM1 to participate in regulating the therapeutic effects of HHT on CRC. Our ndings provide evidence for clinical application of NKD1targeted therapy in improving HHT sensitivity for CRC treatment

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“…There are also differences in the efficacy of ruxolitinib in lymphoid neoplasms with abnormal JAK2 pathway. Recent data (29) reported that an elderly woman diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) with PCM1-JAK2 rearrangement failed to obtain complete cytogenetic and molecular biological response after receiving traditional chemotherapy and immunotherapy. Within 1 year after ruxolitinib 10 mg bid treatment, the PCM1-JAK2 fusion transcript and abnormal metaphase were significantly reduced, but none of them disappeared completely.…”

Section: Discussionmentioning

confidence: 99%

Diagnosis and Treatment of Myeloproliferative Neoplasms With PCM1-JAK2 Rearrangement: Case Report and Literature Review

et al. 2021

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Myeloproliferative neoplasm (MPN) with PCM1-JAK2 rearrangement is a rare disease with poor prognosis and lacks uniform treatment guidelines. Several studies confirmed the efficacy of ruxolitinib in hematological malignancies with PCM1-JAK2 fusion, but the efficacy is variable. Here, we report two patients diagnosed with MPN with PCM1-JAK2 fusion who were treated with ruxolitinib-based regimen, including the first case of ruxolitinib combined with pegylated interferon (Peg-IFN), and we conduct a literature review. We found that ruxolitinib combined with Peg-IFN is an effective treatment option in the case of poor efficacy of ruxolitinib monotherapy.

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Efficacy of ruxolitinib in B‐lymphoblastic leukaemia with the PCM1–JAK2 fusion gene

Cited by 9 publications

References 10 publications

The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia

The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia

NKD1 targeting PCM1 regulates the therapeutic effects of homoharringtonine on colorectal cancer

Diagnosis and Treatment of Myeloproliferative Neoplasms With PCM1-JAK2 Rearrangement: Case Report and Literature Review

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