Partial Response to Sorafenib in a Child With a Myeloid/Lymphoid Neoplasm, Eosinophilia, and a ZMYM2-FLT3 Fusion

Munthe‐Kaas, Monica Cheng; Forthun, Rakel Brendsdal; Brendehaug, Atle; Eek, Anette Kildal; Høysæter, Trude; Osnes, Liv; Prescott, Trine; Spetalen, Signe; Hovland, Randi

doi:10.1097/mph.0000000000001890

Cited by 10 publications

(18 citation statements)

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“…fusion genes are recognized as strong genetic drivers in hematologic malignancies, sometimes even pathognomonic for specific clinical subtypes of disease, and often represent the primary event in the leukemic process, which makes them attractive targets for diagnosis and treatment (21,37). In immunodeficient mice, ZMYM2-FGFR1 alone is capable of initiating a myeloproliferative-like disorder, with increased cellular proliferation, blast accumulation, bone marrow fibrosis, and increased extramedullary hematopoiesis, consistent with features observed in patients with ZMYM2-FGFR1 neoplasms (17,38). Given the recent discovery of ZMYM2-FLT3, no data are available regarding its role in the pathogenesis of hematologic malignancies or its prognostic significance.…”

Section: Discussionmentioning

confidence: 61%

Avadomide Induces Degradation of ZMYM2 Fusion Oncoproteins in Hematologic Malignancies

Renneville

Gasser

Grinshpun

et al. 2021

Blood Cancer Discovery

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Thalidomide analogs exert their therapeutic effects by binding to the CRL4 CRBN E3 ubiquitin ligase, promoting ubiquitination and subsequent proteasomal degradation of specific protein substrates. Drug-induced degradation of IKZF1 and IKZF3 in B-cell malignancies demonstrates the clinical utility of targeting disease-relevant transcription factors for degradation. Here, we found that avadomide (CC-122) induces CRBN-dependent ubiquitination and proteasomal degradation of ZMYM2 (ZNF198), a transcription factor involved in balanced chromosomal rearrangements with FGFR1 and FLT3 in aggressive forms of hematologic malignancies. The minimal drug-responsive element of ZMYM2 is a zinc-chelating MYM domain and is contained in the N-terminal portion of ZMYM2 that is universally included in the derived fusion proteins. We demonstrate that avadomide has the ability to induce proteasomal degradation of ZMYM2-FGFR1 and ZMYM2-FLT3 chimeric oncoproteins, both in vitro and in vivo. Our findings suggest that patients with hematologic malignancies harboring these ZMYM2 fusion proteins may benefit from avadomide treatment. SIGNIFICANCE We extend the potential clinical scope of thalidomide analogs by the identification of a novel avadomide-dependent CRL4 CRBN substrate, ZMYM2. Avadomide induces ubiquitination and degradation of ZMYM2-FGFR1 and ZMYM2-FLT3, two chimeric oncoproteins involved in hematologic malignancies, providing a proof-of-concept for drug-induced degradation of transcription factor fusion proteins by thalidomide analogs.

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Section: Discussionmentioning

confidence: 61%

Avadomide Induces Degradation of ZMYM2 Fusion Oncoproteins in Hematologic Malignancies

Renneville

Gasser

Grinshpun

et al. 2021

Blood Cancer Discovery

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“…MLN-TK with FLT3 fusions remain rare, yet increased recognition of this entity fostered by its recent inclusion in the WHO and ICC classifications of hematologic neoplasms ( Arber et al 2022 ; Khoury et al 2022 ) will allow us to better delineate disease characteristics of this entity. At the time of writing, 34 cases have been reported ( Table 3 ; Vu et al 2006 ; Grand et al 2007 ; Tzankov et al 2008 ; Walz et al 2011 ; Chonabayashi et al 2014 ; Falchi et al 2014 ; Hosseini et al 2014 ; Sato et al 2015 ; Chung et al 2017 ; Jawhar et al 2017 ; Roberts et al 2017 ; Troadec et al 2017 ; Zhang et al 2018 ; Chao et al 2020 ; Shao et al 2020 ; Zhou et al 2020 ; Munthe-Kaas et al 2021 ; Spitzer et al 2021 ; Tang et al 2021 ; Belhassan et al 2022 ; Kurihara et al 2022 ). Although the spectrum of neoplasms with documented FLT3 rearrangements is wide, myeloid malignancies appear overrepresented with a predilection for myeloproliferative neoplasms with eosinophilia (51.6%).…”

Section: Discussionmentioning

confidence: 99%

“…From a treatment perspective, 58.8% of patients received an allogeneic stem cell transplantation and 73.5% required multiagent systemic therapy. A TKI with anti-FLT3 activity (including sunitinib, sorafenib, quizartinib, and gilteritinib) was attempted in 11 patients and at least a partial or transient response to this therapy was achieved in all patients ( Walz et al 2011 ; Falchi et al 2014 ; Jawhar et al 2017 ; Chao et al 2020 ; Shao et al 2020 ; Munthe-Kaas et al 2021 ; Tang et al 2021 ). Patient outcome was variable across reports with 50% of patients succumbing to their disease and 41.2% achieving or maintaining a complete remission at the time of their respective publication.…”

Section: Discussionmentioning

confidence: 99%

“…ETV6 break-apart FISH strategy is only appropriate in the setting of ETV6::FLT3 fusions. ( Munthe-Kaas et al 2021 ). c Information regarding additional mutation testing was available for 19 patients.…”

Section: Discussionmentioning

confidence: 99%

“…ZMYM8::FLT3 fusions maybe be cytogenetically cryptic by conventional chromosome analysis as they involve a 8Mb inversion. ETV6 break-apart FISH strategy is only appropriate in the setting of ETV6::FLT3 fusions (Munthe-Kaas et al 2021).…”

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confidence: 99%

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ATRIP11:: FLT3gene fusion in a patient with myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions: a case report and review of the literature

Venable

Gagnon

Pitel

et al. 2023

Cold Spring Harb Mol Case Stud

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Myeloid/lymphoid neoplasms with FLT3 gene fusions have recently been included among myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) in the World Health Organization classification and International Consensus Classification. As this entity remains remarkably rare, its scope and phenotypic features are evolving. In this report, we describe a 33-year-old male with MLN-TK. Conventional chromosome analysis revealed a t(13;14)(q12;q32). Further analysis with mate-pair sequencing (MPseq) confirmed a TRIP11::FLT3 gene fusion. A diagnosis of MLN-TK was rendered. To the best of our knowledge, we report the third case of MLN-TK with a TRIP11::FLT3 gene fusion. In contrast to previously described cases, our case exhibited distinctly mild clinical features and disease behavior, emphasizing the diverse spectrum of MLN-TK at primary presentation and variability in disease course. MLN-TK with FLT3 gene fusions are a genetically defined entity which may be targetable with tyrosine kinase inhibitors with anti-FLT3 activity. Accordingly, from diagnostic and therapeutic viewpoints, genetic testing for FLT3 rearrangements using FISH or sequencing-based assays should be pursued for patients with chronic eosinophilia.

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The international consensus classification of eosinophilic disorders and systemic mastocytosis

et al. 2023

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Based on new data and increased understanding of disease molecular genetics, the international consensus classification (ICC) has made several changes in the diagnosis and classification of eosinophilic disorders and systemic mastocytosis. Myeloid/lymphoid neoplasms with eosinophilia (M/LN‐eo) and gene rearrangements have been renamed as M/LN‐eo with tyrosine kinase gene fusions (M/LN‐eo‐TK). The category has been expanded to include ETV6::ABL1 and FLT3 fusions, and to accept PCM1::JAK2 and its genetic variants as formal members. The overlaps and differences between M/LN‐eo‐TK and BCR::ABL1‐like B‐lymphoblastic leukemia (ALL)/de novo T‐ALL sharing the same genetic lesions are addressed. Besides genetics, ICC for the first time has introduced bone marrow morphologic criteria in distinguishing idiopathic hypereosinophilia/hypereosinophilic syndrome from chronic eosinophilic leukemia, not otherwise specified. The major diagnostic criteria for systemic mastocytosis (SM) in the ICC remain largely based on morphology, but several minor modifications/refinements have been made in criteria related to diagnosis, subclassification, and assessment of disease burden (B‐ and C‐findings). This review is to focus on the ICC updates related to these disease entities, illustrated through changes related to morphology, molecular genetics, clinical features, prognosis, and treatment. Two practical algorithms are provided in navigating through the diagnosis and classification systems of hypereosinophilia and SM.

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Partial Response to Sorafenib in a Child With a Myeloid/Lymphoid Neoplasm, Eosinophilia, and a ZMYM2-FLT3 Fusion

Cited by 10 publications

References 8 publications

Avadomide Induces Degradation of ZMYM2 Fusion Oncoproteins in Hematologic Malignancies

Avadomide Induces Degradation of ZMYM2 Fusion Oncoproteins in Hematologic Malignancies

ATRIP11:: FLT3gene fusion in a patient with myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions: a case report and review of the literature

The international consensus classification of eosinophilic disorders and systemic mastocytosis

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