Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure

Mossner, Maximilian; Jann, Johann Christoph; Wittig, Janina; Nolte, Florian; Fey, Stéphanie; Nowak, Verena; Obländer, Julia; Pressler, Jovita; Palme, Iris; Xanthopoulos, Christina; Boch, Tobias; Metzgeroth, Georgia; Röhl, Henning; Witt, Stephanie H.; Dukal, Helene; Klein, Corinna; Schmitt, Steffen; Gelß, Patrick; Platzbecker, Uwe; Balaian, Ekaterina; Fabarius, Alice; Blum, Helmut; Schulze, Torsten J.; Meggendorfer, Manja; Haferlach, Claudia; Trumpp, Andreas; Hofmann, Wolf Karsten; Medyouf, Hind; Nowak, Daniel

doi:10.1182/blood-2015-11-679167

Cited by 117 publications

(139 citation statements)

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“…The phenotypic effects seen here with CMML xenotransplantation over a relatively short timeframe are unique given that previously published xenograft models of MDS [31][32][33] and aggressive MPNs such as myelofibrosis 48 do not result in overt phenotypic effects despite engraftment with human diseased cells. The high levels of human engraftment achieved here across numerous tissues with resulting lethality, cytopenias, and hepatosplenomegaly render these models very useful in preclinical evaluation of novel therapeutic approaches for CMML.…”

Section: Discussionmentioning

confidence: 99%

“…26 NSGS and MISTRG mice have already demonstrated improved engraftment of myeloid cells and myeloid cell output of normal CD34 1 cells as well as subtypes of AML that previously engrafted at low rates in NSG mice. [26][27][28][29][30] However, robust xenotransplantation models are still lacking for several chronic myeloid neoplasms, particularly MDS [31][32][33] and CMML. Given the known hypersensitivity of CMML and JMML to GM-CSF, we evaluated engraftment of CMML and JMML in NSGS mice here and identified highly robust engraftment of CD34 1 cells as well as mononuclear cells (MNCs) from BM and peripheral blood (PB) from CMML and JMML patients.…”

Section: Introductionmentioning

confidence: 99%

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Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Yoshimi

Balasis

Vedder

et al. 2017

Blood

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• Genetically accurate xenografts of CMML are achievable with near 100% frequency in NSGS mice.• Robust human engraftment and overt phenotypes of CMML and JMML xenografts here facilitate preclinical therapeutic evaluation in vivo.Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2Rg null background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34 1 cells (n 5 8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n 5 10) resulted in robust engraftment of CMML in BM, spleen, liver, and lung of recipients (n 5 82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34 1 cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD34 1 cells as harboring the disease-initiating compartment in vivo.Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n 5 4 patients, n 5 12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically accurate preclinical models of these disorders. (Blood. 2017;130(4):397-407)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Yoshimi

Balasis

Vedder

et al. 2017

Blood

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“…Progression of MDS into secondary AML has been reported to be linked to clonal evolution, which can be related to the emergence or variations of genomic anomalies 8 . These observations, supported by recent studies [9][10][11] , led us to address the appearance and evolution of TP53-mutated subclones in lower-risk del(5q) MDS patients along the course of the disease. We thus retrospectively screened for TP53 mutations in a cohort of such MDS patients who received lenalidomide in the course of their treatment.…”

mentioning

confidence: 59%

Emergence and evolution of TP53 mutations are key features of disease progression in myelodysplastic patients with lower-risk del(5q) treated with lenalidomide

Lodé

Ménard²,

Flet

et al. 2017

Haematologica

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“…27 The data are also reminiscent to other myeloid neoplasms and their clonal diversity, in which mutations in RUNX1, N/KRAS or IDH2 were also identified as late events and drivers for disease progression. 19,[28][29][30][31] Of interest, no significant increase in clone size was observed for mutations in TET2 or SRSF2, although they represent early mutations in the multistep pathogenesis of SM, 8 chronic myelomonocytic leukemia, 32 or MDS. 19 These results suggest that the extensive clinical heterogeneity of advSM is most likely because of the presence and dynamic evolution of several molecularly disparate subclones, which have a variable impact on clinical characteristics and response to treatment.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19][20] The sequential NGS approach is based on library preparation by the Access Array Technology (Fluidigm, San Francisco, CA) and sequencing on the MiSeq Instrument (Illumina, San Diego, CA). Gene mutations were annotated using the reference sequence of the Ensembl Transcript ID (Ensembl release 85: July 2016).…”

Section: Targeted Next-generation Sequencing (Ngs) Analysismentioning

confidence: 99%

Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers

Jawhar

Schwaab

Naumann

et al. 2017

Blood

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101

102

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Key Points• The complexity and dynamics of mutations significantly impact on response, progression, and prognosis in midostaurintreated advSM patients.In advanced systemic mastocytosis (advSM), disease evolution is often triggered by KIT mutations (D816V in >80% of cases) and by additional mutations (eg, in SRSF2, ASXL1, and/or RUNX1 [S/A/R pos in >60% of cases]). In a recently reported phase 2 study, midostaurin, a multikinase/KIT inhibitor, demonstrated an overall response rate (ORR) of 60% in advSM but biomarkers predictive of response are lacking. We evaluated the impact of molecular markers at baseline and during follow-up in 38 midostaurin-treated advSM patients. The median overall survival (OS) was 30 months (95% confidence interval, 6-54) from start of midostaurin. ORR and OS were significantly different between S/A/R neg (n 5 12) and S/A/R pos (n 5 23) patients (ORR: 75% vs 39%, P 5 .04; OS: P 5 .01, HR 4.5 [1.3-16.2]). Depending on the relative reduction of the KIT D816V expressed allele burden (EAB) at month 6, patients were classified as KIT responders ( ‡25%, n 5 17) or KIT nonresponders (<25%, n 5 11). In univariate analyses at month 6, reduction of KIT D816V EAB ‡25%, tryptase ‡50%, and alkaline phosphatase ‡50% were significantly associated with improved OS. In multivariate analysis, only KIT D816V EAB reduction ‡25% remained an independent on-treatment marker for improved OS (P 5 .004,). Serial next-generation sequencing analysis of 28 genes in 16 patients revealed acquisition of additional mutations or increasing variant allele frequency in K/NRAS, RUNX1, IDH2, or NPM1 associated with progression in 7 patients. In midostaurin-treated advSM patients, the complexity and dynamics of mutational profiles significantly affect response, progression, and prognosis. (Blood. 2017;130(2):137-145)

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Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure

Abstract: Key Points Mutational trajectories are defined by complex patterns of molecular heterogeneity in MDS, including lower-risk cases. Therapeutic intervention dynamically reshapes mutational patterns often resulting in branched or independent evolution of MDS clones.

Cited by 117 publications

References 50 publications

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Emergence and evolution of TP53 mutations are key features of disease progression in myelodysplastic patients with lower-risk del(5q) treated with lenalidomide

Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers

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