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1.
Blood ; 142(24): 2079-2091, 2023 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-37595362

RESUMEN

PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of PPM1D in hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover a central role for Ppm1d in hematopoiesis and validate its potential as a therapeutic target. We find that Ppm1d regulates the competitive fitness and self-renewal of hematopoietic stem cells (HSCs) with and without exogenous genotoxic stresses. We also show that although Ppm1d activation confers cellular resistance to cytotoxic therapy, it does so to a lesser degree than p53 loss, informing the clonal competition phenotypes often observed in human studies. Notably, loss of Ppm1d sensitizes leukemias to cytotoxic therapies in vitro and in vivo, even in the absence of a Ppm1d mutation. Vulnerability to PPM1D inhibition is observed across many cancer types and dependent on p53 activity. Importantly, organism-wide loss of Ppm1d in adult mice is well tolerated, supporting the tolerability of pharmacologically targeting PPM1D. Our data link PPM1D gain-of-function mutations to the clonal expansion of HSCs, inform human genetic observations, and support the therapeutic targeting of PPM1D in cancer.


Asunto(s)
Daño del ADN , Proteína p53 Supresora de Tumor , Adulto , Humanos , Animales , Ratones , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína Fosfatasa 2C , Mutación , Monoéster Fosfórico Hidrolasas/genética , Ciclo Celular
2.
Haematologica ; 109(2): 422-430, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-37584291

RESUMEN

Monosomy 7 is the most common cytogenetic abnormality in pediatric myelodysplastic syndrome (MDS) and associated with a high risk of disease progression. However, in young children, spontaneous loss of monosomy 7 with concomitant hematologic recovery has been described, especially in the presence of germline mutations in SAMD9 and SAMD9L genes. Here, we report on our experience of close surveillance instead of upfront hematopoietic stem cell transplantation (HSCT) in seven patients diagnosed with SAMD9L syndrome and monosomy 7 at a median age of 0.6 years (range, 0.4-2.9). Within 14 months from diagnosis, three children experienced spontaneous hematological remission accompanied by a decrease in monosomy 7 clone size. Subclones with somatic SAMD9L mutations in cis were identified in five patients, three of whom attained hematological remission. Two patients acquired RUNX1 and EZH2 mutations during the observation period, of whom one progressed to myelodysplastic syndrome with excess of blasts (MDS-EB). Four patients underwent allogeneic HSCT at a median time of 26 months (range, 14-40) from diagnosis for MDSEB, necrotizing granulomatous lymphadenitis, persistent monosomy 7, and severe neutropenia. At last follow-up, six patients were alive, while one passed away due to transplant-related causes. These data confirm previous observations that monosomy 7 can be transient in young children with SAMD9L syndrome. However, they also indicate that delaying HSCT poses a substantial risk of severe infection and disease progression. Finally, surveillance of patients with SAMD9L syndrome and monosomy 7 is critical to define the evolving genetic landscape and to determine the appropriate timing of HSCT (clinicaltrials gov. Identifier: NCT00662090).


Asunto(s)
Deleción Cromosómica , Síndromes Mielodisplásicos , Humanos , Niño , Preescolar , Lactante , Remisión Espontánea , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Progresión de la Enfermedad , Factores de Transcripción/genética , Monosomía , Cromosomas Humanos Par 7/genética , Péptidos y Proteínas de Señalización Intracelular/genética
3.
Pediatr Hematol Oncol ; 37(6): 530-538, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32374222

RESUMEN

PEG asparaginase is an important and established drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). Severe hypertriglyceridemia is a rare complication of PEG asparaginase in combination with glucocorticoids. We report a case of excessive hypertriglyceridemia in a child during ALL induction therapy successfully treated by lipid apheresis and give a literature review on the management of hypertriglyceridemia in children treated for ALL.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Eliminación de Componentes Sanguíneos , Hipertrigliceridemia , Quimioterapia de Inducción/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Asparaginasa/administración & dosificación , Asparaginasa/efectos adversos , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Humanos , Hipertrigliceridemia/sangre , Hipertrigliceridemia/inducido químicamente , Hipertrigliceridemia/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia
4.
J Vis Exp ; (203)2024 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-38345255

RESUMEN

Single-cell sequencing has enabled the mapping of heterogeneous cell populations in the stroma of hematopoietic organs. These methodologies provide a lens through which to study previously unresolved heterogeneity at steady state, as well as changes in cell type representation induced by extrinsic stresses or during aging. Here, we present step-wise protocols for the isolation of high-quality stromal cell populations from murine and human thymus, as well as murine bone and bone marrow. Cells isolated through these protocols are suitable for generating high-quality single-cell multiomics datasets. The impacts of sample digestion, hematopoietic lineage depletion, FACS analysis/sorting, and how these factors influence compatibility with single-cell sequencing are discussed here. With examples of FACS profiles indicating successful and inefficient dissociation and downstream stromal cell yields in post-sequencing analysis, recognizable pointers for users are provided. Considering the specific requirements of stromal cells is crucial for acquiring high-quality and reproducible results that can advance knowledge in the field.


Asunto(s)
Médula Ósea , Células del Estroma , Humanos , Animales , Ratones , Citometría de Flujo , Células del Estroma/metabolismo , Células Madre Hematopoyéticas , Células de la Médula Ósea/metabolismo
5.
Nat Commun ; 15(1): 4325, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38773071

RESUMEN

Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigate how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we find that the epigenetic features of clones at similar differentiation status are highly heterogeneous and functionally respond differently to Tet2 mutation. Cell differentiation stage also influences Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitizes cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.


Asunto(s)
Proteínas de Unión al ADN , Dioxigenasas , Epigénesis Genética , Células Madre Hematopoyéticas , Mutación , Proteínas Proto-Oncogénicas , Dioxigenasas/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Animales , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Humanos , Hematopoyesis/genética , Ratones , Diferenciación Celular/genética
6.
J Natl Cancer Inst ; 115(8): 981-988, 2023 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-37042724

RESUMEN

BACKGROUND: The expansion of hematopoietic stem cells carrying recurrent somatic mutations, termed clonal hematopoiesis (CH), is common in elderly individuals and is associated with increased risk of myeloid malignancy and all-cause mortality. Though chemotherapy is a known risk factor for developing CH, how myelosuppressive therapies affect the short-term dynamics of CH remains incompletely understood. Most studies have been limited by retrospective design, heterogeneous patient populations, varied techniques to identifying CH, and analysis of single timepoints. METHODS: We examined serial samples from 40 older women with triple-negative or hormone receptor-positive breast cancer treated on the prospective ADjuVANt Chemotherapy in the Elderly trial to evaluate the prevalence and dynamics of CH at baseline and throughout chemotherapy (6 and 12 weeks). RESULTS: CH was detected in 44% of patients at baseline and in 53% at any timepoint. Baseline patient characteristics were not associated with CH. Over the course of treatment, mutations exhibited a variety of dynamics, including emergence, expansion, contraction, and disappearance. All mutations in TP53 (n = 3) and PPM1D (n = 4), genes that regulate the DNA damage response, either became detectable or expanded over the course of treatment. Neutropenia was more common in patients with CH, particularly when the mutations became detectable during treatment, and CH was significantly associated with cyclophosphamide dose reductions and holds (P = .02). CONCLUSIONS: Our study shows that CH is common, dynamic, and of potential clinical significance in this population. Our results should stimulate larger efforts to understand the biological and clinical importance of CH in solid tumor malignancies. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03858322). Clinical trial registration number: NCT03858322.


Asunto(s)
Neoplasias de la Mama , Hematopoyesis Clonal , Humanos , Femenino , Anciano , Hematopoyesis Clonal/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Estudios Retrospectivos , Hematopoyesis/genética , Mutación
7.
J Clin Med ; 10(14)2021 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-34300250

RESUMEN

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric leukemia characterized by mutations in five canonical RAS pathway genes. The diagnosis is made by typical clinical and hematological findings associated with a compatible mutation. Although this is sufficient for clinical decision-making in most JMML cases, more in-depth analysis can include DNA methylation class and panel sequencing analysis for secondary mutations. NRAS-initiated JMML is heterogeneous and adequate management ranges from watchful waiting to allogeneic hematopoietic stem cell transplantation (HSCT). Upfront azacitidine in KRAS patients can achieve long-term remissions without HSCT; if HSCT is required, a less toxic preparative regimen is recommended. Germline CBL patients often experience spontaneous resolution of the leukemia or exhibit stable mixed chimerism after HSCT. JMML driven by PTPN11 or NF1 is often rapidly progressive, requires swift HSCT and may benefit from pretransplant therapy with azacitidine. Because graft-versus-leukemia alloimmunity is central to cure high risk patients, the immunosuppressive regimen should be discontinued early after HSCT.

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