Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia

Nakata, Yoshihisa; Ueda, Takeshi; Nagamachi, Akiko; Yamasaki, Norimasa; Ikeda, Kenichiro; Sera, Yasuyuki; Takubo, Keiyo; Kanai, Akinori; Oda, Hideaki; Sanada, Masashi; Ogawa, Seishi; Tsuji, Kohichiro; Ebihara, Yasuhiro; Wolff, Linda; Honda, Zen‐ichiro; Suda, Toshio; Inaba, Toshiya; Honda, Hiroaki

doi:10.1182/blood-2016-06-724658

Cited by 23 publications

(17 citation statements)

References 53 publications

(65 reference statements)

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“…A JAK2 inhibitor was reported to be effective in a mouse model of Cbl-deficient chronic myelomonocytic leukemia expressing JAK2. 27 Together with the results of previous studies, our findings raised a question regarding the activity of JAK2 inhibitors in TSGCT patients with CBL mutations. These inhibitors currently have therapeutic applications in the treatment of myelofibrosis or inflammatory diseases such as rheumatoid arthritis.…”

Section: Discussionsupporting

confidence: 75%

“…Our analysis demonstrated that CBL mutations were associated with enhanced JAK2 expression and poor local disease control. A JAK2 inhibitor was reported to be effective in a mouse model of Cbl ‐deficient chronic myelomonocytic leukemia expressing JAK2 . Together with the results of previous studies, our findings raised a question regarding the activity of JAK2 inhibitors in TSGCT patients with CBL mutations.…”

Section: Discussionmentioning

confidence: 99%

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Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations

Tsuda

Hirata

Katayama

et al. 2019

Intl Journal of Cancer

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Tenosynovial giant cell tumor (TSGCT) is a rare neoplasm. Although surgical resection is the widely accepted primary treatment for TSGCT, recurrences are frequent, and patients’ joint function may be severely compromised. Previous studies reported that CSF1‐COL6A3 fusion genes were identified in approximately 30% of TSGCTs. The aim of our study was to comprehensively clarify the genomic abnormalities in TSGCTs. We performed whole exome sequencing in combination with target sequence validation on 34 TSGCT samples. RNA sequencing was also performed on 18 samples. RNA sequencing revealed fusion transcripts involving CSF1, including novel CSF1‐VCAM1, CSF1‐FN1 and CSF1‐CDH1 fusions, in 13/18 (72%) cases. These fusion genes were validated by chromogenic in situ hybridization. All CSF1 fusions resulted in the deletion of CSF1 exon 9, which was previously shown to be an important negative regulator of CSF1 expression. We also found that 12 (35%) of the 34 TSGCT samples harbored CBL missense mutations. All mutations were detected in exons 8 or 9, which encode the linker and RING finger domain. Among these mutations, C404Y, L380P and R420Q were recurrent. CBL‐mutated cases showed higher JAK2 expression than wild‐type CBL cases (p = 0.013). CSF1 fusion genes and CBL mutations were not mutually exclusive, and both alterations were detected in six of the 18 (33%) tumors. The frequent deletion of CSF1 exon 9 in the fusion transcripts suggested the importance of this event in the etiology of TSGCT. Our results may contribute to the development of new targeted therapies using JAK2 inhibitors for CBL‐mutated TSGCT.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations

Tsuda

Hirata

Katayama

et al. 2019

Intl Journal of Cancer

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“…Unlike other studies that observed hyperactivation of MAPK, JAK-STAT and PI3K/AKT pathways (2,6,15,23,24,28,(35)(36)(37)(38)(39)(40)(41), our global characterization of tyrosine phosphorylation in cells expressing mutant CBL revealed selective activation of LYN and the PI3K/AKT pathway; in fact, tyrosine phosphorylation sites that directly indicate activation of the MAPK or STAT5 pathways were lower in our CBL mutant cells by MS analysis. There are several potential explanations for this discrepancy.…”

Section: Discussioncontrasting

confidence: 95%

“…Consistent with the genetics of CBL mutations in myeloid malignancies, missense mutations in the RING domain of murine Cbl promoted the development of a myeloproliferative disorder that was not observed in Cbl knockout mice (22)(23)(24).…”

Section: Introductionmentioning

confidence: 59%

“…Second, the effects of CBL mutations may depend on the cellular context. Along these lines, hematopoietic stem and progenitor cells from Cbl mutant mice showed increased PI3K/AKT, MAP kinase and STAT5 signaling, though there were differences in the signaling effects depending on the subpopulation analyzed (24). Third, two studies evaluated the effects of CBL mutants on a Cbl -/-/Cblb -/genetic background (35,41), which has the potential to augment or alter the signaling phenotype conferred by CBL mutant protein due to functional redundancy between Cbl and Cblb in mice (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

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CBL mutations promote activation of PI3K/AKT signaling via LYN kinase

Belizaire

Koochaki

Udeshi

et al. 2020

Preprint

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CBL encodes an E3 ubiquitin ligase and signaling adaptor that acts downstream of cytokine receptors. Recurrent CBL mutations occur in myeloid malignancies, but the mechanism by which these mutations drive oncogenesis remains incompletely understood. Here we performed a series of studies to define the phosphoproteome, CBL interactome and molecular mechanisms of signaling activation in cells expressing an allelic series of CBL mutants. Our analyses revealed that increased LYN activation and interaction with mutant CBL are key drivers of enhanced PIK3R1 recruitment and downstream PI3K/AKT signaling in CBL-mutant cells. Furthermore, we demonstrated in vitro and in vivo efficacy of LYN inhibition by dasatinib in CBL-mutant cell lines and primary chronic myelomonocytic leukemia cells. Overall, our data provide rationale for exploring the therapeutic potential of LYN inhibition in patients with CBL-mutated myeloid malignancies. Statement of SignificanceWe investigated the oncogenic mechanisms of myeloid malignancy-associated CBL mutations by mass spectrometry-based proteomics and interactomics. Our findings indicate that increased LYN kinase activity in CBL-mutant cells stimulates PI3K/AKT signaling, revealing opportunities for the use of targeted inhibitors in CBL-mutated myeloid malignancies.

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The Noncanonical RAS/MAPK Pathway and the RASopathies

Mo,

Castel

2024

The RASopathies

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Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia

Abstract: Key Points Acquired expression of CblQ367P induces sustained proliferation of myelomonocytes, multilineage dysplasia, and splenomegaly resembling CMML. Combined inhibition of PI3K and JAK2 efficiently suppressed the growth of CblQ367P-induced CMML cells.

Cited by 23 publications

References 53 publications

Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations

Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations

CBL mutations promote activation of PI3K/AKT signaling via LYN kinase

The Noncanonical RAS/MAPK Pathway and the RASopathies

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