A Humanized Animal Model Predicts Clonal Evolution and Therapeutic Vulnerabilities in Myeloproliferative Neoplasms

Celik, Hamza; Krug, Ethan; Zhang, Christine Rc; Han, Wentao; Issa, Nancy; Koh, Won Kyun; Bjeije, Hassan; Kukhar, Ostap; Allen, Maggie J.; Li, Tindao; Fisher, Daniel A.C.; Fowles, Jared S.; Wong, Terrence N.; Stubbs, Matthew C.; Koblish, Holly K.; Oh, Stephen T.; Challen, Grant A.

doi:10.1101/2020.11.12.378810

Cited by 6 publications

(5 citation statements)

References 52 publications

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“…Lastly, we adopted patient-derived xenograft (PDX) humanized mouse models, which we have previously demonstrated to maintain patient genetic hierarchy and disease features. 21-23 Purified CD34 + cells from 2 unique MF patients were transplanted into NSGS mice, and treatment with pevonedistat alone or in combination with ruxolitinib was initiated following confirmation of successful engraftment. For PDX1 (patient MF530675), PB hCD45 + cell engraftment was inhibited by pevonedistat or ruxolitinib monotherapy, with combination treatment being superior to ruxolitnib alone ( Figure 6A ).…”

Section: Resultsmentioning

confidence: 99%

Section: Pevonedistat Alone or In Combination With Ruxolitinib Potently Alleviates Disease Burden Across Multiple Mpn And Saml Mouse Modementioning

confidence: 99%

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Pevonedistat targets malignant cells in myeloproliferative neoplasms in vitro and in vivo via NFκB pathway inhibition

Kong¹,

Laranjeira²,

Collins³

et al. 2022

Blood Advances

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Targeted inhibitors of JAK2 (e.g. ruxolitinib) often provide symptomatic relief for myeloproliferative neoplasm (MPN) patients, but the malignant clone persists and remains susceptible to disease transformation. These observations suggest that targeting alternative dysregulated signaling pathways may provide therapeutic benefit. Previous studies identified NFϰB pathway hyperactivation in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML) that was insensitive to JAK2 inhibition. Here, we provide evidence that NFϰB pathway inhibition via pevonedistat targets malignant cells in MPN patient samples as well as in MPN and patient-derived xenograft mouse models that is non-redundant with ruxolitinib. Colony forming assays revealed preferential inhibition of MF colony growth compared to normal colony formation. In mass cytometry studies, pevonedistat blunted canonical TNFα responses in MF and sAML patient CD34+ cells. Pevonedistat also inhibited hyperproduction of inflammatory cytokines more effectively than ruxolitinib. Upon pevonedistat treatment alone or in combination with ruxolitinib, MPN mouse models exhibited reduced disease burden and improved survival. These studies demonstrating efficacy of pevonedistat in MPN cells in vitro as well as in vivo provide a rationale for therapeutic inhibition of NFϰB signaling for MF treatment. Based on these findings, a Phase I clinical trial combining pevonedistat with ruxolitinib has been initiated.

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Section: Resultsmentioning

confidence: 99%

Section: Pevonedistat Alone or In Combination With Ruxolitinib Potently Alleviates Disease Burden Across Multiple Mpn And Saml Mouse Modementioning

confidence: 99%

Pevonedistat targets malignant cells in myeloproliferative neoplasms in vitro and in vivo via NFκB pathway inhibition

Kong¹,

Laranjeira²,

Collins³

et al. 2022

Blood Advances

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“…Spleens were weighed at endpoint and normalized to mouse body weight at endpoint. sAML patient-derived xenograft (PDX) models PDX models were performed following protocol as previously described (32,33). Briefly, PBMCs from sAML patients were isolated by Ficoll gradient extraction and CD34+ cells were isolated using magnetic enrichment (Miltenyi Biotec #130-100-453) and cultured overnight in SFEMII media (StemCell Technologies #09605) supplemented with Pen-Strep (50 Units/mL), human stem cell factor (SCF; 50 ng/mL), human thrombopoietin (TPO; 50 ng/mL), and human FLT3L (50 ng/mL).…”

Section: Mpl W515l Modelmentioning

confidence: 99%

DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression

et al. 2022

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Chronic myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed bulk transcriptome profiling accompanied by single cell RNA-sequencing on CD34+ stem/progenitor cells from serial patient samples obtained at the chronic MPN and sAML phases, and identified aberrantly increased expression of dual-specificity phosphatase 6 (DUSP6) underlying disease transformation. Genetic and pharmacologic targeting of DUSP6 led to inhibition of S6 and JAK/STAT signaling, resulting in potent suppression of cell proliferation, while also reducing inflammatory cytokine production in primary samples. Furthermore, ectopic DUSP6 expression augmented proliferation and mediated JAK2 inhibitor resistance, while DUSP6 inhibition reduced colony-forming potential of JAK2 inhibitor-persistent patient cells.Mechanistically, DUSP6 perturbation dampened S6 signaling via inhibition of RSK1, which we identified as a second indispensable candidate associated with poor clinical outcome. Lastly, DUSP6 inhibition potently suppressed disease development across Jak2 V617F and MPL W515L MPN mouse models, and sAML patient-derived xenografts. These findings underscore DUSP6 in driving disease transformation and therapeutic resistance, and highlight the DUSP6-RSK1 axis as a novel, druggable pathway in myeloid malignancies.

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“…disease is polyclonal and driven by a single mutation), and response to experimental therapeutics. With that said it is worth noting that while MPN research has not readily been able to take advantage of NSG xenograft models for assessing primary MPN patient cell sensitivity to experiment therapeutics, advances in this space as demonstrated by Jayavelu et al [ 64 ] and others [ 99 ] are providing exciting evidence that such assessment is possible and may afford distinct advantages over other commonly used MPN mouse models.…”

Section: Discussionmentioning

confidence: 99%

JAK2 inhibitor persistence in MPN: uncovering a central role of ERK activation

2022

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The Philadelphia chromosome negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocytosis, and myelofibrosis, are driven by hyper activation of the JAK2 tyrosine kinase, the result of mutations in three MPN driving genes: JAK2, MPL, and CALR. While the anti-inflammatory effects of JAK2 inhibitors can provide improved quality of life for many MPN patients, the upfront and persistent survival of disease-driving cells in MPN patients undergoing JAK2 inhibitor therapy thwarts potential for remission. Early studies indicated JAK2 inhibitor therapy induces heterodimeric complex formation of JAK2 with other JAK family members leading to sustained JAK2-dependent signaling. Recent work has described novel cell intrinsic details as well as cell extrinsic mechanisms that may contribute to why JAK2 inhibition may be ineffective at targeting MPN driving cells. Diverse experimental strategies aimed at uncovering mechanistic details that contribute to JAK2 inhibitor persistence have each highlighted the role of MEK/ERK activation. These approaches include, among others, phosphoproteomic analyses of JAK2 signaling as well as detailed assessment of JAK2 inhibition in mouse models of MPN. In this focused review, we highlight these and other studies that collectively suggest targeting MEK/ERK in combination with JAK2 inhibition has the potential to improve the efficacy of JAK2 inhibitors in MPN patients. As MPN patients patiently wait for improved therapies, such studies should further strengthen optimism that pre-clinical research is continuing to uncover mechanistic insights regarding the ineffectiveness of JAK2 inhibitors, which may lead to development of improved therapeutic strategies.

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A Humanized Animal Model Predicts Clonal Evolution and Therapeutic Vulnerabilities in Myeloproliferative Neoplasms

Cited by 6 publications

References 52 publications

Pevonedistat targets malignant cells in myeloproliferative neoplasms in vitro and in vivo via NFκB pathway inhibition

Pevonedistat targets malignant cells in myeloproliferative neoplasms in vitro and in vivo via NFκB pathway inhibition

DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression

JAK2 inhibitor persistence in MPN: uncovering a central role of ERK activation

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