ABSTRACT
Cell stemness is characterized by quiescence, pluripotency, and long-term self-renewal capacity. Therapy-resistant leukemic stem cells (LSCs) are the primary cause of relapse in patients with chronic and acute myeloid leukemia (CML and AML). However, the same signaling pathways frequently support stemness in both LSCs and normal hematopoietic stem cells (HSCs), making LSCs difficult to therapeutically target. In cell lines and patient samples, we found that interleukin-33 (IL-33) signaling promoted stemness only in leukemia cells in a subtype-specific manner. The IL-33 receptor ST2 was abundant on the surfaces of CD34+ BCR/ABL1 CML and CD34+ AML cells harboring AML1/ETO and DEK/NUP214 translocations or deletion of chromosome 9q [del(9q)]. The cell surface abundance of ST2, which was lower or absent on other leukemia subtypes and HSCs, correlated with stemness, activated Wnt signaling, and repressed Notch signaling. IL-33-ST2 signaling promoted the maintenance and expansion of AML1/ETO-, DEK/NUP214-, and BCR/ABL1-positive LSCs in culture and in mice by activating Wnt, MAPK, and NF-κB signaling. Wnt signaling and its inhibition of the Notch pathway up-regulated the expression of the gene encoding ST2, thus forming a cell-autonomous loop. IL-33-ST2 signaling promoted the resistance of CML cells to the tyrosine kinase inhibitor (TKI) nilotinib and of AML cells to standard chemotherapy. Thus, inhibiting IL-33-ST2 signaling may target LSCs to overcome resistance to chemotherapy or TKIs in these subtypes of leukemia.
Subject(s)
Interleukin-33 , Leukemia, Myeloid , Animals , Mice , Interleukin-1 Receptor-Like 1 Protein , Interleukin-33/genetics , NF-kappa B , Wnt Signaling PathwayABSTRACT
Patients with acute myeloid leukemia (AML) frequently relapse after chemotherapy, yet the mechanism by which AML reemerges is not fully understood. Herein, we show that primary AML cells enter a senescence-like phenotype following chemotherapy in vitro and in vivo. This is accompanied by induction of senescence/inflammatory and embryonic diapause transcriptional programs, with downregulation of MYC and leukemia stem cell genes. Single-cell RNA sequencing suggested depletion of leukemia stem cells in vitro and in vivo, and enrichment for subpopulations with distinct senescence-like cells. This senescence effect was transient and conferred superior colony-forming and engraftment potential. Entry into this senescence-like phenotype was dependent on ATR, and persistence of AML cells was severely impaired by ATR inhibitors. Altogether, we propose that AML relapse is facilitated by a senescence-like resilience phenotype that occurs regardless of their stem cell status. Upon recovery, these post-senescence AML cells give rise to relapsed AMLs with increased stem cell potential. SIGNIFICANCE: Despite entering complete remission after chemotherapy, relapse occurs in many patients with AML. Thus, there is an urgent need to understand the relapse mechanism in AML and the development of targeted treatments to improve outcome. Here, we identified a senescence-like resilience phenotype through which AML cells can survive and repopulate leukemia.This article is highlighted in the In This Issue feature, p. 1307.
Subject(s)
Leukemia, Myeloid, Acute/drug therapy , Neoplasm Recurrence, Local/drug therapy , Neoplastic Stem Cells/cytology , Remission Induction , Animals , Cell Line, Tumor/cytology , Humans , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Inbred NOD , Neoplasm Recurrence, Local/pathology , PhenotypeABSTRACT
Only 50% of patients with relapsed Hodgkin lymphoma (HL) can be cured with intensive induction chemotherapy, followed by high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). Based on the results of the HDR2 trial two courses of DHAP and subsequent HDCT/ASCT are the current standard of care in relapsed HL. In order to assess the prognostic relevance of DHAP dose density, we performed a retrospective multivariate analysis of the HDR2 trial (N=266). In addition to four risk factors (early or multiple relapse, stage IV disease or anemia at relapse, and grade IV hematotoxicity during the first cycle of DHAP) a delayed start of the second cycle of DHAP>day 22 predicted a significantly poorer progression-free survival (PFS, p=0.0356) and overall survival (OS, p=0.0025). In conclusion, our analysis strongly suggests that dose density of DHAP has a relevant impact on the outcome of relapsed HL patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hodgkin Disease/drug therapy , Hodgkin Disease/mortality , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/adverse effects , Cisplatin/therapeutic use , Combined Modality Therapy , Cytarabine/adverse effects , Cytarabine/therapeutic use , Dexamethasone/adverse effects , Dexamethasone/therapeutic use , Female , Germany , Hematopoietic Stem Cell Transplantation , Hodgkin Disease/pathology , Humans , Male , Middle Aged , Neoplasm Staging , Prognosis , Proportional Hazards Models , Radiotherapy, Adjuvant , Recurrence , Retreatment , Salvage Therapy , Treatment OutcomeABSTRACT
An International Working Group met to revise the diagnostic and response criteria for acute myelogenous leukemia originally published in 1990, as well as to provide definitions of outcomes and reporting standards to improve interpretability of data and comparisons among trials. Since the original publication, there have been major advances in our understanding of the biology and molecular genetics of acute leukemia that are clinically relevant and warrant incorporation into response definitions. Differences from the 1990 recommendations included a category of leukemia-free state, new criteria for complete remission, including cytogenetic and molecular remissions and remission duration. Storage of viable blasts for correlative studies is important for future progress in the therapy of these disorders.
