PRDM16s transforms megakaryocyte-erythroid progenitors into myeloid leukemia–initiating cells

Hu, Tianyuan; Morita, Kiyomi; Hill, Matthew C.; Jiang, Yajian; Kitano, Ayumi; Saito, Yûsuke; Wang, Feng; Mao, Xizeng; Hoegenauer, Kevin A.; Morishita, Kazuhiro; Martin, James F.; Futreal, P. Andrew; Takahashi, Koichi; Nakada, Daisuke

doi:10.1182/blood.2018888255

Cited by 17 publications

(16 citation statements)

References 69 publications

(86 reference statements)

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“…It failed to show benefit in treating VOEs, although it was shown to prevent VOEs and to normalize blood flow in animal studies. 30 Both drugs were ineffective at treating VOEs and accelerating recovery, in agreement with the concept that P-selectin inhibition is not an effective strategy after a VOE has set in. Recently, crizanlizumab—a monoclonal antibody that inhibits P-selectin function—was studied for its prophylactic use and yielded positive results that led to regulatory approval.…”

Section: P-selectin Inhibition In Humans With Scdsupporting

confidence: 69%

P-Selectin Blockade in the Treatment of Painful Vaso-Occlusive Crises in Sickle Cell Disease: A Spotlight on Crizanlizumab

Karki¹,

Kutlar²

2021

JPR

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Microvascular vaso-occlusion driven pain crisis is the hallmark of sickle cell disease with profound morbidity and increased mortality. Selectins, most notably P-selectins have an integral role in this phenomenon. P-selection was first identified in 1989. In 2019, after 3 decades of basic, translational, and clinical work with this pathway, the US Food and Drug Administration approved a P-selectin antibody, crizanlizumab to reduce frequency of pain crisis in patients more than 16 years with sickle cell disease. We review the fundamentals of P-selectin pathobiology, P-selectin blocking agents, clinical data with the use of crizanlizumab and prospects of this novel class of drugs in the context of other treatments for painful vaso-occlusive episodes.

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Section: P-selectin Inhibition In Humans With Scdsupporting

confidence: 69%

P-Selectin Blockade in the Treatment of Painful Vaso-Occlusive Crises in Sickle Cell Disease: A Spotlight on Crizanlizumab

Karki¹,

Kutlar²

2021

JPR

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“…This shorter isoform of Prdm16 is also preferentially activated by retroviral insertions causing immortalization of myeloid progenitors (10). Mechanistically, direct activation of Spi1 by the shorter isoform has been recently shown to be critical for its transformation of megakaryocyte-erythroid progenitors into leukemia stem cells for AML development (11). In contrast, the fulllength form has been shown to antagonize leukemia development through activating Gfi1b (8,12).…”

mentioning

confidence: 99%

Prdm16 is a critical regulator of adult long-term hematopoietic stem cell quiescence

Gudmundsson

Nguyen

Oakley

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of quiescence is critical for the maintenance of adult hematopoietic stem cells (HSCs). Disruption of transcription factor gene Prdm16 during mouse embryonic development has been shown to cause a severe loss of fetal liver HSCs; however, the underlying mechanisms and the function of Prdm16 in adult HSCs remain unclear. To investigate the role of Prdm16 in adult HSCs, we generated a novel conditional knockout mouse model and deleted Prdm16 in adult mouse hematopoietic system using the IFN-inducible Mx1-Cre. Our results show that Prdm16 deletion in the adult mouse hematopoietic system has a less severe effect on HSCs, causing a gradual decline of adult HSC numbers and a concomitant increase in the multipotent progenitor (MPP) compartment. Prdm16 deletion in the hematopoietic system following transplantation produced the same phenotype, indicating that the defect is intrinsic to adult HSCs. This HSC loss was also exacerbated by stress induced by 5-fluorouracil injections. Annexin V staining showed no difference in apoptosis between wild-type and knockout adult HSCs. In contrast, Bromodeoxyuridine analysis revealed that loss of Prdm16 significantly increased cycling of long-term HSCs (LT-HSCs) with the majority of the cells found in the S to G2/M phase. Consistently, RNA sequencing analysis of mouse LT-HSCs with and without Prdm16 deletion showed that Prdm16 loss induced a significant decrease in the expression of several known cell cycle regulators of HSCs, among which Cdkn1a and Egr1 were identified as direct targets of Prdm16. Our results suggest that Prdm16 preserves the function of adult LT-HSCs by promoting their quiescence.

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“…In addition it is associated with other gene fusions not investigated here [42]. Hu et al [43] reported that PRDM16 transforming megakaryocyte-erythroid progenitors into myeloid leukemia stem cells. In another study, PRDM16 knockdown induced cell proliferation in rhabdoid tumor cells [44], suggesting that PRDM16 may be an oncogene in leukemia development, although in other tumor types PRDM16 has a controversial role [45,46].…”

Section: Discussionmentioning

confidence: 85%

Identifying novel genetic alterations in pediatric acute lymphoblastic leukemia based on copy number analysis

et al. 2020

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Copy number variations (CNVs) analysis may reveal molecular biomarkers and provide information on the pathogenesis of acute lymphoblastic leukemia (ALL). We investigated the gene copy number in childhood ALL by microarray and select three new recurrent CNVs to evaluate by real-time PCR assay: DMBT1, KIAA0125 and PRDM16 were selected due to high frequency of CNVs in ALL samples and based on their potential biological functions in carcinogenesis described in the literature. DBMT1 deletion was associated with patients with chromosomal translocations and is a potential tumor suppressor; KIAA0125 and PRDM16 may act as an oncogene despite having a paradoxical behavior in carcinogenesis. This study reinforces that microarrays/aCGH is it is a powerful tool for detection of genomic aberrations, which may be used in the risk stratification.

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PRDM16s transforms megakaryocyte-erythroid progenitors into myeloid leukemia–initiating cells

Cited by 17 publications

References 69 publications

P-Selectin Blockade in the Treatment of Painful Vaso-Occlusive Crises in Sickle Cell Disease: A Spotlight on Crizanlizumab

P-Selectin Blockade in the Treatment of Painful Vaso-Occlusive Crises in Sickle Cell Disease: A Spotlight on Crizanlizumab

Prdm16 is a critical regulator of adult long-term hematopoietic stem cell quiescence

Identifying novel genetic alterations in pediatric acute lymphoblastic leukemia based on copy number analysis

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