Transdifferentiation of lymphoma into sarcoma associated with profound reprogramming of the epigenome

Zhang, Qian; Orlando, Elena; Wang, Hong Y; Bogusz, Agata M.; Liu, Xiaobin; Lacey, Simon F.; Strauser, Honore T.; Nuñez-Cruz, Selene; Nejati, Reza; Zhang, Paul; Brooks, Sarah; Watt, Christopher D.; Melenhorst, J. Joseph; June, Carl H.; Schuster, Stephen J.; Wasik, Mariusz A.

doi:10.1182/blood.2020005123

Cited by 25 publications

(23 citation statements)

References 24 publications

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“…In relapse seen after 50 days of treatment with standard T-ALL chemotherapy, AML signatures were seen. This patient also showed another switch from AML to T-ALL when subjected to bone marrow transplant followed by second round of therapy[103]. This switch from T-ALL to AML has also been observed in vitro and also in vivo mouse models.…”

supporting

confidence: 64%

“…Another instance of therapy-driven lineage switch was observed in a patient with a twelve-year history of mantle cell lymphoma (MCL). Upon administration of autologous chimeric-antigen receptor T-cells targeting CD19 (CART19) therapy, a switch from MCL into poorly differentiated sarcoma was observed[103].Treatment-induced stress can also drive switch from myeloid to lymphocytic lineage. For instance, imatinib treatment for a CML patient revealed B-lymphoblastic leukemia through bone marrow study and immunophenotyping by flow cytometry[107].…”

mentioning

confidence: 99%

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Lineage Plasticity in Cancer: The Tale of a Skin-walker

Thankamony¹,

Subbalakshmi²,

Jolly³

et al. 2021

Preprint

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Lineage plasticity, the switching of cells from one lineage to another has been recognized to be a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their advantage, resulting in tumorigenesis, relapse, metastasis and therapy resistance. In this review, we summarize our current understanding on the role of lineage plasticity in tumor progression and therapeutic resistance in multiple cancers. Lineage plasticity can be triggered by treatment itself and is reported across various solid as well as liquid tumors. Here we focus on the importance of lineage switching in tumor progression and therapeutic resistance of solid tumors such as the prostate, lung, hepatocellular and colorectal carcinoma and the myeloid and lymphoid lineage switch observed in leukemias. Besides this, we also discuss the role of Epithelial-Mesenchymal Transition (EMT) in facilitating the lineage switch in biphasic cancers such as aggressive carcinosarcomas. We also discuss the mechanisms involved, current therapeutic approaches and challenges that lie ahead in taming the scourge of lineage plasticity in cancer.

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supporting

confidence: 64%

mentioning

confidence: 99%

Lineage Plasticity in Cancer: The Tale of a Skin-walker

Thankamony¹,

Subbalakshmi²,

Jolly³

et al. 2021

Preprint

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“…146 Of note, a recent report describes an MCL patient whose tumour underwent transdifferentiation to a poorly differentiated sarcoma that was confirmed to be clonally related to the initial MCL by IgH sequencing. 147 Therefore, in lymphoma, as in B-ALL, targeting multiple antigens with CART may reduce the incidence of relapse. As understood from chemotherapy regimens, simultaneous targeting rather than sequential treatment is expected to prevent resistance.…”

Section: Antigen-negative Relapsementioning

confidence: 99%

CAR‐T TREK through the lymphoma universe, to boldly go where no other therapy has gone before

et al. 2020

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Chimeric antigen receptor (CAR) T cells (CART) therapies have changed and continue to change the treatment paradigms for B-cell malignancies because they can achieve durable complete remission in patients in whom multiple lines of treatment have failed. These unprecedented results have led to the widespread use of anti-CD19 CART therapy for patients with relapsed and refractory aggressive large B-cell lymphomas. While long-term follow-up data show that about one-third of patients achieve prolonged complete remission and are potentially cured, the majority of patients either do not respond to CD19 CART therapy or eventually relapse after CD19 CART therapy. These results are, on the one hand, driving intense research into identifying mechanisms of relapse and, on the other hand, inspiring the development of novel strategies to overcome resistance. This review summarizes current clinical outcomes of CART immunotherapy in B-cell non-Hodgkin lymphomas, describes the most upto-date understanding of mechanisms of relapse and discusses novel strategies to address resistance to CART therapy. We are indeed at the beginning of a scientific trek to explore the mechanisms of resistance, seek out new, more effective treatment approaches based on these discoveries and to boldly go where no other therapy has gone before!

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“…Additionally, transdifferentiation between lymphoma and sarcoma may occur through cellular reprogramming, potentially initiated by hematopoietic disruption. 67 In this light, it is especially interesting that a shared region of the canine genome was found to be significantly associated with B-cell lymphomas and hemangiosarcomas of golden retrievers. 43…”

Section: Discussionmentioning

confidence: 99%

Hemangiosarcoma Cells Promote Conserved Host-Derived Hematopoietic Expansion

Kim

Schulte

Sarver

et al. 2021

Preprint

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Hemangiosarcoma and angiosarcoma are soft tissue sarcomas of malignant blood vessel-forming cells in dogs and humans, respectively. These vasoformative sarcomas are aggressive and highly metastatic, with disorganized, irregular blood-filled vascular spaces. Our objective was to define molecular programs that support the niche, enabling progression of canine hemangiosarcoma and human angiosarcoma. Here, we show that the transcriptional landscape of canine hemangiosarcoma and human angiosarcoma included comparable angiogenic and inflammatory programs. Dog-in-mouse hemangiosarcoma xenografts recapitulated the vasoformative and highly angiogenic morphology and molecular characteristics of primary tumors. Blood vessels in the tumors were complex and disorganized, and they were lined by both donor and host cells, a trait that was not observed in xenografts from canine osteosarcoma and lymphoma. In some cases, the xenografted hemangiosarcoma cells created exuberant myeloid hyperplasia and gave rise to lymphoproliferative tumors of mouse origin. We did not uncover a definitive transmissible etiology, but our data indicate that transcriptional programs of hemangiosarcoma cells resemble those of hematopoietic nurse cells, and these malignant cells support expansion and differentiation of human hematopoietic progenitors. We conclude that canine hemangiosarcoma, and possibly human angiosarcoma, originate from nurse cells that make up the stromal bone marrow niche, and that these cells may also support the growth of hematopoietic tumors.

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Transdifferentiation of lymphoma into sarcoma associated with profound reprogramming of the epigenome

Cited by 25 publications

References 24 publications

Lineage Plasticity in Cancer: The Tale of a Skin-walker

Lineage Plasticity in Cancer: The Tale of a Skin-walker

CAR‐T TREK through the lymphoma universe, to boldly go where no other therapy has gone before

Hemangiosarcoma Cells Promote Conserved Host-Derived Hematopoietic Expansion

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