Acute myeloid leukemia (AML) is a disease with great morphological and genetic heterogeneity, which complicates its prognosis and treatment. The hypomethylating agents azacitidine (Vidaza®, AZA) and decitabine (Dacogen®, DAC) have been approved for the treatment of AML patients, but their mechanisms of action are poorly understood. Natural killer (NK) cells play an important role in the recognition of AML blasts through the interaction of the activating NKG2D receptor with its ligands (NKG2DL: MICA/B and ULBPs1-3). However, soluble NKG2DL (sNKG2DL) can be released from the cell surface, impairing immune recognition. Here, we examined whether hypomethylating agents modulate the release of sNKG2DL from AML cells. Results demonstrated that AZA- and DAC-treated AML cells reduce the release of sNKG2DL, preventing downregulation of NKG2D receptor on the cell surface and promoting immune recognition mediated by NKG2D-NKG2DL engagement. We show that the shedding of MICA, MICB and ULBP2 is inhibited by the increased expression of TIMP3, an ADAM17 inhibitor, after DAC treatment. The TIMP3 gene is highly methylated in AML cells lines and in AML patients (25.5%), in which it is significantly associated with an adverse cytogenetic prognosis of the disease. Overall, TIMP3 could be a target of the demethylating treatments in AML patients, leading to a decrease in MICA, MICB and ULBP2 shedding and the enhancement of the lytic activity of NK cells through the immune recognition mediated by the NKG2D receptor.

NKG2D

Azacitidine

Decitabine

Demethylating agent

10.18632/oncotarget.16657

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Citations (44)

Should prophylactic granulocyte‐colony stimulating factor be used in multiple myeloma patients developing neutropenia under lenalidomide‐based therapy?

British Journal of Haematology (2007)

María‐Victoria Mateos Ramón García‐Sánz Enrique Colado Juan Olazábal L.Jesús F. San Miguel

Summary Lenalidomide combined with dexamethasone has significant clinical activity in the treatment of multiple myeloma (MM). In previous clinical trials lenalidomide‐induced neutropenia was a frequent side‐effect, often leading to treatment delays and dose reductions. We describe three MM patients treated with lenalidomide plus dexamethasone, which developed grade 3/4 neutropenia during the initial cycles, but without serious infection. Administration of granulocyte‐colony stimulating factor (G‐CSF) for 3 d prevented further neutropenia, treatment delays, dose reductions, or infectious complications during the following cycles. Consequently, G‐CSF could be effective in preventing further neutropenia‐related complications without compromising treatment efficacy in MM patients with lenalidomide‐induced neutropenia.

10.1111/j.1365-2141.2007.06946.x

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The mutational landscape of small lymphocytic lymphoma compared to non-early stage chronic lymphocytic leukemia

Leukemia & lymphoma/Leukemia and lymphoma (2017)

Alejandra Martínez‐Trillos Magda Pinyol Julio Delgado Marta Aymerich Marı́a Rozman

Small lymphocytic lymphoma (SLL) is considered as the non-leukemic form of presentation of chronic lymphocytic leukemia (CLL). We have compared the features, genomic alterations, and outcome of 890 patients with CLL and SLL. One hundred and thirteen patients presented as SLL and more frequently had unmutated-IGHV, CD38high, ZAP-70high, CD49dhigh, +12, alterations in genes of NOTCH1, cell cycle, RNA metabolism, and NFkB pathways than CLL. During the follow-up, 46% of SLL patients developed CLL. Time to first treatment (TTFT) was shorter in SLL (10-year: 75% vs 62%; p = .006). Binet stage, SLL, and IGHV were independent predictive factors for TTFT. Transformation to diffuse large B-cell lymphoma was higher (10-year: 12% vs 6%; p = .003), and overall survival was shorter in SLL (10-year: 55% vs 66%; p = .004). When A0 CLL patients were excluded, only CD38 and CD49d expression, +12, and 10-year TTFT remained different between the SLL and CLL patients. In summary, SLL showed only minor clinicobiological differences when compared with CLL in similar clinical stages.

IGHV@

10.1080/10428194.2017.1397660

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Routine flow cytometry approach for the evaluation of solid tumor neoplasms and immune cells in minimally invasive samples

Cytometry Part B Clinical Cytometry (2022)

C. Quirós Tamara Arias Ariana Fonseca‐Mourelle Héctor Enrique Torres Rivas L. Fernández

Multidimensional flow cytometry (MFC) is routinely used for the diagnosis and follow-up of hematolymphoid neoplasms but its contribution to the identification of non-hematolymphoid malignant tumors is limited.The presence of non-hematolymphoid cells in clinical samples obtained via minimally invasive methods was ascertained by using a panel of monoclonal antibodies previously developed in our laboratory comprising a mixture of antibodies: CD9-PacB/CD45-OC515/CD57-FITC/CD56-PE/CD3-PerCP-Cy5.5/CD117-PE-Cy7/CD326-APC/CD81-APC-C750. Histopathological studies were performed using standard techniques.164 specimens of different origins were included. Malignancy was finally confirmed in 142 (86.5%), while 22 non neoplastic samples were identified. The most frequent diagnosis was small cell lung carcinoma (SCLC) (50%). High sensitivity (S = 98.6%) was reached combining MFC and conventional pathology. Individual markers differed according to the cellular origin of the neoplasm, with neuroendocrine tumors showing a unique immunophenotypic profile (CD56+ CD326+ CD117-/+ and variable tetraspanins expression). Principal component analysis efficiently distinguished SCLC from other tumor samples. In immune cell populations, differences between reactive and malignant biopsies were found in different cell compartments, especially in B cells and Plasma cells. Differences also emerged in the percentage of CD4+ CD8- T cells, CD4-CD8+ T cells and NK cells and these were dependent on the origin of the tumor cells.These results support the use of MFC as a rapid and valuable technique to detect non-hematolymphoid tumoral cells in clinical specimens, providing an initial orientation to complement hystopathological studies and allow a more precise diagnosis, especially in neuroendocrine neoplasms. The impact of different immune cell patterns warrants further research.

CD117

10.1002/cyto.b.22081

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Azacitidine in older patients with acute myeloid leukemia (AML). Results from the ALMA study according to the MRC risk index score.

Journal of Clinical Oncology (2015)

José Falantes Violeta Martinez Robles Joan Bargay Guillermo Debén Ana Garrido

7061 Background: Treatment of patients (pts) >60y with AML remains challenging. The MRC and LRF validated a 1y survival risk index score in 2843 older AML pts treated with intensive (IC) and non-intensive (NI) chemotherapy, identifying 3 groups with different risk estimates1. Azacitidine (AZA) prolonged OS in older AML pts vs. conventional care (AZA-AML-001 trial)2. Nevertheless, comparison between AZA and IC was jeopardized by the low number of subjects randomized to AZA or IC. Aim: To assess the impact of AZA in a retrospective cohort of older AML pts, unfit for IC, stratified by the MRC/LRF risk score. Methods: The ALMA cohort accrued 110 unfit AML pts who received compassionate front-line AZA before 2011 in 22 Spanish sites (Ramos F et al, Leuk Res. 2014). Cytogenetic, age, white blood count (WBC), PS and AML type categorized pts as good, standard and poor-risk, as stated by Wheatley’s score. Results: Characteristics of the ALMA cohort and distribution across MRC/LRF risk categories are shown in Table 1. After accounting for the above 5 parameters, the ALMA cohort included more poor-risk pts than the MRC/LRF series (63% vs. 31%/37% in the AML11/AML14 trials, respectively). After 28 months median follow-up, 1y survival of ALMA cohort was 66%, 40% and 31%, respectively, for the good, standard and poor-risk groups. Comparison of these estimates with those of MRC/LRF trials are also shown in Table 1. Potentially relevant clinical differences are apparent in the poor-risk group when comparing AZA to either approach. Conclusions: Although retrospective and non-matched, AML pts unfit for IC seemed to benefit from AZA to a similar extent to IC. Moreover, in the poor-risk subset (n=70), 1y survival with AZA was equivalent and likely superior to previous AML/MRC strategies. ALMA cohort. Parameter N (%) Age (median) 75 (56-89) PS 0-1: 77 2: 27 >2: 6 WCB (<109/L) 79 (72) Therapy-related AML & AHD 16 (14%) & 27 (24.5%) MRC cytogenetics Fav: 1 (0.9) Inter: 64 (58.2) Adv: 30 (27.3) NA: 15 (13.6) Risk categories (AML11 risk) Good: 7 (6.4) Standard: 33 (30) Poor: 70 (63.6) 1y survival estimates (%) MRC/LRF Risk group AML11 AML14I AML14NI AML14NIA AML14 (all) ALMA Good 53 60 25 36 59 66 Standard 43 48 33 42 45 40 Poor 16 30 10 14 24 31

Azacitidine

10.1200/jco.2015.33.15_suppl.7061

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Newly diagnosed adult AML and MPAL patients frequently show clonal residual hematopoiesis

Leukemia (2013)

Carlos Fernández Maria Cláudia Santos‐Silva Antonio López Sergio Matarraz María Jara‐Acevedo

Myelopoiesis

Minimal Residual Disease

Immunophenotyping

10.1038/leu.2013.109

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Citations (13)

Diagnóstico y tratamiento de la hemoglobinuria paroxística nocturna

Medicina Clínica (2010)

Álvaro Urbano-Ispízua Anna Gayà Enrique Colado Montserrat López Beatriz Arrizabalaga

10.1016/j.medcli.2010.07.017

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Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment

Zenodo (CERN European Organization for Nuclear Research) (2018)

Rocío G. Urdinguio Virginia López Gustavo F. Bayón Rafael Díaz de la Guardia Marta Sierra

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.

Histone H4

Compartment (ship)

10.5281/zenodo.2425053

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