Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia

Ebinger, Sarah; Özdemir, Erbey Ziya; Ziegenhain, Christoph; Tiedt, Sebastian; Alves, Catarina Castro; Grunert, M; Dworzak, Michael; Lutz, Christoph; Turati, Virginia; Enver, Tariq; Horny, Hans‐Peter; Sotlar, Karl; Parekh, Swati; Spiekermann, Karsten; Hiddemann, Wolfgang; Schepers, Aloys; Polzer, Bernhard; Kirsch, Stefan; Hoffmann, Martin; Knapp, Bettina L.; Hasenauer, Jan; Pfeifer, Heike; Panzer‐Grümayer, Renate; Enard, Wolfgang; Gires, Olivier; Jeremias, Irmela

doi:10.1016/j.ccell.2016.11.002

Cited by 230 publications

(319 citation statements)

References 42 publications

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“…A recent experimental study, modeling diagnosis and relapse ALL, suggests that relapse initiates from dormant leukemic cells that survive by adhering to protective bone-marrow stroma cells (63). According to this model, initial chemotherapy eliminates the bulk of leukemic cells (e.g., JAK and RAS mutated cells).…”

Section: Discussionmentioning

confidence: 99%

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Schwartzman

Savino

Gombert

et al. 2017

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

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Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DSALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/ RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are "relapse driving." We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2 pos DSALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2 pos , Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT "hypersignaling" may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL.C hildren with Down syndrome (DS) are at a markedly increased risk for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) (1). The poor survival of DS-ALL compared with ALL in children without DS ("sporadic" ALL) is related to increased treatment toxicity and to increased incidence of relapse (2). Thus, better therapy is needed for these patients.Previous studies by our group and others revealed differences between the genetics of DS-ALLs and of sporadic ALLs (3-6). The typical cytogenetic subgroups, ETV6-RUNX1 and hyperdiploid ALLs, are less common in DS-ALLs. Acquired somatic activation of the thymic stromal lymphopoietin (TSLP) pathway are present at diagnosis in about half of DS-ALLs. Aberrant expression of cytokine receptor-like factor 2 (CRLF2) in these leukemias is caused by chromosomal rearrangements consisting either of a microdeletion on chromosome X, juxtaposing the promoter of P2RY8 with the coding region of CRLF2, or by a translocation of CRLF2 into the Ig heavy chain (IgH) locus. CRLF2 heterodimerizes with IL7 receptor-α (IL7R) to form the receptor to TSLP (reviewed in ref. 7). TSLP receptors signal by activation of the JAK-STAT pathway. Interestingly, in the majority of DS-ALLs, SignificanceChildren with Down syndrome are at increased risk ...

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Section: Discussionmentioning

confidence: 99%

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Schwartzman

Savino

Gombert

et al. 2017

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

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“…Altogether, these characteristics suggested that late events could originate from a subpopulation of relapse-inducing cells exhibiting properties of long-term dormancy and stemness, as recently isolated from pediatric and adult patients with minimal residual disease (MRD). 45 These cells also displayed in vivo drug resistance due to limited proliferation when located in their niche and were sensitive when dissociated from this protective environment. 45 Overall, if confirmed in other cohorts, our results have direct clinical implications considering that rapid subclonal expansion and high tumor plasticity are key determinants of rapid cALL evolution and predictive factors of early therapeutic escapes.…”

Section: Discussionmentioning

confidence: 99%

Mutational dynamics of early and late relapsed childhood ALL: rapid clonal expansion and long-term dormancy

et al. 2018

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Key Points• Two distinct evolutionary patterns govern early and late relapse.• Evolutionary patterns suggest a mutationdriven resistance for early relapses and a reexpansion of dormant cells for late ones.Childhood acute lymphoblastic leukemia (cALL) is the most frequent pediatric cancer.Refractory/relapsed cALL presents a survival rate of ;45% and is still one of the leading causes of death by disease among children. Mechanisms, such as clonal competition and evolutionary adaptation, govern treatment resistance. However, the underlying clonal dynamics leading to multiple relapses and differentiating early (,36 months postdiagnosis) from late relapse events remain elusive. Here, we use an integrative genome-based analysis combined with serial sampling of relapsed tumors (from primary tumor to #4 relapse events) from 19 pre-B-cell cALL patients (8 early and 11 late relapses) to assess the fitness of somatic mutations and infer their ancestral relationships. By quantifying both general clonal dynamics and newly acquired subclonal diversity, we show that 2 distinct evolutionary patterns govern early and late relapse: on one hand, a highly dynamic pattern, sustained by a putative defect of DNA repair processes, illustrating the quick emergence of fitter clones, and on the other hand, a quasi-inert evolution pattern, suggesting the escape from dormancy of leukemia stem cells likely spared from initial cytoreductive therapy.These results offer new insights into cALL relapse mechanisms and highlight the pressing need for adapted treatment strategies to circumvent resistance mechanisms.

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“…Overall, this provides valuable powerful tools to explore cancer evolution and progression, as demonstrated in a study of Ding et al who reported that the mutations acquired by a breast PDTX across different generations could be found in the metastatic sites [31]. A similar scenario has been described in leukemia PDTX models [32].…”

Section: Pdtx Generation and Characterizationmentioning

confidence: 68%

“…On the same line, Ebinger S. et al have isolated a subclone from PDTX derived from rare relapse-inducing cells of acute lymphoblastic leukemia (ALL) that show dormancy, therapy resistance and stem-like properties. By using single-cell RNASeq data, the authors revealed substantial similarity with primary ALL cells isolated from pediatric and adult patients at minimal residual disease (MRD) [32]. Using this later approach, Kim et al were able to demonstrate a candidate tumor cell subgroup associated with anti-cancer drug resistance in viable lung adenocarcinoma in PDTX [48].…”

Section: Pdtx In Basic Cancer Research Modeling Tumor Heterogeneity Amentioning

confidence: 99%

Patient-Derived-Tumor-Xenograft: modeling cancer for basic and translational cancer research

Fiore¹,

Giacomo²,

Kyriakides³

et al. 2017

Clin Diagn Pathol

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Patient-Derived-Tumor-Xenografts (PDTX) represent one of the most promising platforms to model human cancer and its complexity. PDTX are able to closely recapitulate the principal features of donor tumors, and remain fairly stable along the passages, rendering them an ideal tool to serve as powerful and predictive models in oncology. Here we aimed to overview our current understanding of PDTX, and their potential applications in basic and translational cancer research. We briefly describe the methodological aspects of PDTX generation, and then focus on the usefulness of PDTX in tumor heterogeneity and clonal evolution studies, as well as their usage to dissect the host microenvironment and the emergence of drug resistance. We also focus on the key role of PDTX in the discovery of biomarkers and drug screening development. The limitations and future perspectives to further improve the PDTX models are also discussed.

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Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia

Cited by 230 publications

References 42 publications

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Mutational dynamics of early and late relapsed childhood ALL: rapid clonal expansion and long-term dormancy

Patient-Derived-Tumor-Xenograft: modeling cancer for basic and translational cancer research

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