Try a new search

Format these results:

Searched for:

person:cimmil01

in-biosketch:yes

Total Results:

41


Tracking the Evolution of Therapy-Related Myeloid Neoplasms Using Chemotherapy Signatures

Diamond, Benjamin T; Ziccheddu, Bachisio; Maclachlan, Kylee H; Taylor, Justin; Boyle, Eileen Mary; Arango Ossa, Juan Esteban; Jahn, Thomas Jacob; Affer, Maurizio; Totiger, Tulasigeri M; Coffey, David G; Chandhok, Namrata; Watts, Justin M; Cimmino, Luisa; Lu, Sydney X; Bolli, Niccolo; Bolton, Kelly L; Landau, Heather J; Park, Jae H; Ganesh, Karuna; McPherson, Andrew; Sekeres, Mikkael A; Lesokhin, Alexander M; Chung, David J; Zhang, Yanming; Ho, Caleb; Roshal, Mikhail; Tyner, Jeffrey W; Nimer, Stephen D; Papaemmanuil, Elli; Usmani, Saad Z; Morgan, Gareth J; Landgren, Ola; Maura, Francesco
Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Pre-leukemic clones (i.e., clonal hematopoiesis; CH) are detectable years before the development of these aggressive malignancies, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are hypermutated and enriched for complex structural variants (i.e., chromothripsis) while neoplasms with non-mutagenic chemotherapy exposures are genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to a discrete clinical exposure in each patient's life, we estimate that several complex events and genomic drivers are acquired after chemotherapy is administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes melphalan exposure and is selected following reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA-damage. Overall, we reveal a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select pre-existing CH, but also promote the acquisition of recurrent genomic drivers.
PMID: 36626250
ISSN: 1528-0020
CID: 5434332

Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia

Brabson, John P; Leesang, Tiffany; Yap, Yoon Sing; Wang, Jingjing; Lam, Minh Q; Fang, Byron; Dolgalev, Igor; Barbieri, Daniela A; Strippoli, Victoria; Bañuelos, Carolina P; Mohammad, Sofia; Lyon, Peter; Chaudhry, Sana; Donich, Dane; Swirski, Anna; Roberts, Evan; Diaz, Ivelisse; Karl, Daniel; Dos Santos, Helena Gomes; Shiekhattar, Ramin; Neel, Benjamin G; Nimer, Stephen D; Verdun, Ramiro E; Bilbao, Daniel; Figueroa, Maria E; Cimmino, Luisa
TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.
PMCID:9989506
PMID: 36848231
ISSN: 2211-1247
CID: 5467302

Corrigendum to "Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis" [Biomater. 161 (2018) 164-178]

Cui, Xin; Tan Morales, Renee-Tyler; Qian, Weiyi; Wang, Haoyu; Gagner, Jean-Pierre; Dolgalev, Igor; Placantonakis, Dimitris; Zagzag, David; Cimmino, Luisa; Snuderl, Matija; Lam, Raymond H W; Chen, Weiqiang
PMID: 35797856
ISSN: 1878-5905
CID: 5280552

Tonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome

Marié, Isabelle J; Brambilla, Lara; Azzouz, Doua; Chen, Ze; Baracho, Gisele V; Arnett, Azlann; Li, Haiyan S; Liu, Weiguo; Cimmino, Luisa; Chattopadhyay, Pratip; Silverman, Gregg; Watowich, Stephanie S; Khor, Bernard; Levy, David E
Maintenance of immune homeostasis involves a synergistic relationship between the host and the microbiome. Canonical interferon (IFN) signaling controls responses to acute microbial infection, through engagement of the STAT1 transcription factor. However, the contribution of tonic levels of IFN to immune homeostasis in the absence of acute infection remains largely unexplored. We report that STAT1 KO mice spontaneously developed an inflammatory disease marked by myeloid hyperplasia and splenic accumulation of hematopoietic stem cells. Moreover, these animals developed inflammatory bowel disease. Profiling gut bacteria revealed a profound dysbiosis in the absence of tonic IFN signaling, which triggered expansion of TH17 cells and loss of splenic Treg cells. Reduction of bacterial load by antibiotic treatment averted the TH17 bias and blocking IL17 signaling prevented myeloid expansion and splenic stem cell accumulation. Thus, tonic IFNs regulate gut microbial ecology, which is crucial for maintaining physiologic immune homeostasis and preventing inflammation.
PMCID:8376249
PMID: 34378531
ISSN: 2050-084x
CID: 5010792

Clinical responsiveness to All-trans Retinoic Acid is potentiated by LSD1 inhibition and associated with a quiescent transcriptome in myeloid malignancies

Tayari, Mina Masoumeh; Gomes Dos Santos, Helena; Kwon, Deukwoo; Bradley, Terrence; Thomassen, Amber; Chen, Charles Jeng; Dinh, Yvonne; Perez, Aymee; Zelent, Artur; Morey, Lluis; Cimmino, Luisa; Shiekhattar, Ramin; Swords, Ronan T; Watts, Justin M
PURPOSE/OBJECTIVE:In preclinical studies, the LSD1 inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-APL acute myeloid leukemia (AML). We conducted a Phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). EXPERIMENTAL DESIGN/METHODS:Seventeen patients were treated with ATRA and TCP (3 dose levels: 10 mg twice daily [BID], 20 mg BID, and 30 mg BID). RESULTS:expression, compared to non-responders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid (RA)-target genes in responders but not non-responders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response. CONCLUSIONS:These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of MDS and AML patients.
PMID: 33495312
ISSN: 1557-3265
CID: 4767032

Epigenetic Regulation of Genomic Stability by Vitamin C

Brabson, John P; Leesang, Tiffany; Mohammad, Sofia; Cimmino, Luisa
DNA methylation plays an important role in the maintenance of genomic stability. Ten-eleven translocation proteins (TETs) are a family of iron (Fe2+) and α-KG -dependent dioxygenases that regulate DNA methylation levels by oxidizing 5-methylcystosine (5mC) to generate 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). These oxidized methylcytosines promote passive demethylation upon DNA replication, or active DNA demethylation, by triggering base excision repair and replacement of 5fC and 5caC with an unmethylated cytosine. Several studies over the last decade have shown that loss of TET function leads to DNA hypermethylation and increased genomic instability. Vitamin C, a cofactor of TET enzymes, increases 5hmC formation and promotes DNA demethylation, suggesting that this essential vitamin, in addition to its antioxidant properties, can also directly influence genomic stability. This review will highlight the functional role of DNA methylation, TET activity and vitamin C, in the crosstalk between DNA methylation and DNA repair.
PMCID:8129186
PMID: 34017357
ISSN: 1664-8021
CID: 4877672

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

Lyon, Peter; Strippoli, Victoria; Fang, Byron; Cimmino, Luisa
Vitamins B9 (folate) and B12 are essential water-soluble vitamins that play a crucial role in the maintenance of one-carbon metabolism: a set of interconnected biochemical pathways driven by folate and methionine to generate methyl groups for use in DNA synthesis, amino acid homeostasis, antioxidant generation, and epigenetic regulation. Dietary deficiencies in B9 and B12, or genetic polymorphisms that influence the activity of enzymes involved in the folate or methionine cycles, are known to cause developmental defects, impair cognitive function, or block normal blood production. Nutritional deficiencies have historically been treated with dietary supplementation or high-dose parenteral administration that can reverse symptoms in the majority of cases. Elevated levels of these vitamins have more recently been shown to correlate with immune dysfunction, cancer, and increased mortality. Therapies that specifically target one-carbon metabolism are therefore currently being explored for the treatment of immune disorders and cancer. In this review, we will highlight recent studies aimed at elucidating the role of folate, B12, and methionine in one-carbon metabolism during normal cellular processes and in the context of disease progression.
PMID: 32961717
ISSN: 2072-6643
CID: 4605672

Novel combinations to improve hematopoiesis in myelodysplastic syndrome

Syed, Khaja; Naguib, Sara; Liu, Zhao-Jun; Cimmino, Luisa; Yang, Feng-Chun
Myelodysplastic syndrome (MDS) represents a heterogeneous group of clonal hematopoietic disorders, which is characterized by cytopenias in the peripheral blood and bone marrow dysplasia due to ineffective hematopoiesis. Patients with MDS have an increased risk of transformation to acute myeloid leukemia (AML). Although the molecular basis of MDS is heterogeneous, several studies demonstrated the significant contribution of the dysregulated immune system in accelerating MDS progression. The immunosuppressive tumor microenvironment is shown to induce tolerance of MDS blasts, which may result in a further accumulation of genetic aberrations and lead to the disease progression. Increasing evidence shows an expansion of myeloid-derived suppressor cells (MDSCs), a population of inflammation-associated immature cells, in patients with MDS. Interestingly, the increased MDSC populations are shown to be correlated with a risk of disease progression in MDS. In addition, MDS is highly prevalent in aged individuals with non-hematology co-morbidities who are fragile for chemotherapy. Increasing research effort is devoting to identify novel agents to specific targeting of the MDSC population for MDS treatment.
PMCID:7083030
PMID: 32197634
ISSN: 1757-6512
CID: 4357322

Spontaneous remission of acute myeloid leukemia with NF1 alteration

Bradley, Terrence; Zuquello, Radames Adamo; Aguirre, Luis E; Mackrides, Nicholas; Chapman, Jennifer; Cimmino, Luisa; Thomassen, Amber; Watts, Justin
Acute myeloid leukemia (AML) is defined by the presence of ≥ 20% myeloblasts in the blood or bone marrow. Spontaneous remission (SR) of AML is a rare event, with few cases described in the literature. SR is generally associated with recovery from an infectious or immunologic process, and more recently possibly with clonal hematopoiesis. We review the literature and assess the trends associated with SR, and report a new case of a 58-year-old man with a morphologic diagnosis of AML associated with a severe gastrointestinal (GI) tract infection. The patient had an NF1 variant that was previously unreported in AML as the only clonal abnormality.  After treatment of the infection, the increased blast population subsided with no leukemia-directed therapy, and the patient has remained in a continuous, spontaneous complete remission for > 2 years.
PMCID:7251391
PMID: 32477862
ISSN: 2213-0489
CID: 4468592

Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia

McKenzie, Mark D; Ghisi, Margherita; Oxley, Ethan P; Ngo, Steven; Cimmino, Luisa; Esnault, Cécile; Liu, Ruijie; Salmon, Jessica M; Bell, Charles C; Ahmed, Nouraiz; Erlichster, Michael; Witkowski, Matthew T; Liu, Grace J; Chopin, Michael; Dakic, Aleksandar; Simankowicz, Emilia; Pomilio, Giovanna; Vu, Tina; Krsmanovic, Pavle; Su, Shian; Tian, Luyi; Baldwin, Tracey M; Zalcenstein, Daniela A; DiRago, Ladina; Wang, Shu; Metcalf, Donald; Johnstone, Ricky W; Croker, Ben A; Lancaster, Graeme I; Murphy, Andrew J; Naik, Shalin H; Nutt, Stephen L; Pospisil, Vitek; Schroeder, Timm; Wall, Meaghan; Dawson, Mark A; Wei, Andrew H; de Thé, Hugues; Ritchie, Matthew E; Zuber, Johannes; Dickins, Ross A
Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states.
PMID: 31374198
ISSN: 1875-9777
CID: 4010102