scholarly journals PHF6 Mutations in Hematologic Malignancies

2021 ◽  
Vol 11 ◽  
Author(s):  
Jason H. Kurzer ◽  
Olga K. Weinberg

Next generation sequencing has uncovered several genes with associated mutations in hematologic malignancies that can serve as potential biomarkers of disease. Keeping abreast of these genes is therefore of paramount importance in the field of hematology. This review focuses on PHF6, a highly conserved epigenetic transcriptional regulator that is important for neurodevelopment and hematopoiesis. PHF6 serves as a tumor suppressor protein, with PHF6 mutations and deletions often implicated in the development of T-lymphoblastic leukemia and less frequently in acute myeloid leukemia and other myeloid neoplasms. PHF6 inactivation appears to be an early event in T-lymphoblastic leukemogenesis, requiring cooperating events, including NOTCH1 mutations or overexpression of TLX1 and TLX3 for full disease development. In contrast, PHF6 mutations tend to occur later in myeloid malignancies, are frequently accompanied by RUNX1 mutations, and are often associated with disease progression. Moreover, PHF6 appears to play a role in lineage plasticity within hematopoietic malignancies, with PHF6 mutations commonly present in mixed phenotype acute leukemias with a predilection for T-lineage marker expression. Due to conflicting data, the prognostic significance of PHF6 mutations remains unclear, with a subset of studies showing no significant difference in outcomes compared to malignancies with wild-type PHF6, and other studies showing inferior outcomes in certain patients with mutated PHF6. Future studies are necessary to elucidate the role PHF6 plays in development of T-lymphoblastic leukemia, progression of myeloid malignancies, and its overall prognostic significance in hematopoietic neoplasms.

Reports ◽  
2019 ◽  
Vol 2 (3) ◽  
pp. 18 ◽  
Author(s):  
Miller ◽  
Park ◽  
Saxe ◽  
Lew ◽  
Raikar

Lineage switch in acute leukemias is a well-reported occurrence; however, most of these cases involve a switch from either lymphoid to myeloid or myeloid to lymphoid lineage. Here, we report a case of a 14-year-old male with B-cell acute lymphoblastic leukemia (B-ALL) who initially responded well to standard chemotherapy but then later developed mixed phenotype acute leukemia (MPAL) at relapse, likely reflecting a clonal evolution of the original leukemia with a partial phenotypic shift. The patient had a del(9)(p13p21) in his leukemia blasts at diagnosis, and the deletion persisted at relapse along with multiple additional cytogenetic aberrations. Interestingly, the patient presented with an isolated testicular lesion at relapse, which on further analysis revealed both a lymphoid and myeloid component. Unfortunately, the patient did not respond well to treatment at relapse and eventually succumbed to his disease. To our knowledge, an isolated extramedullary MPAL at relapse in a patient with previously diagnosed B-ALL has not been reported in the literature before.


2019 ◽  
Vol 20 (12) ◽  
pp. 2929 ◽  
Author(s):  
Nicoletta Coccaro ◽  
Luisa Anelli ◽  
Antonella Zagaria ◽  
Giorgina Specchia ◽  
Francesco Albano

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and accounts for about a quarter of adult acute leukemias, and features different outcomes depending on the age of onset. Improvements in ALL genomic analysis achieved thanks to the implementation of next-generation sequencing (NGS) have led to the recent discovery of several novel molecular entities and to a deeper understanding of the existing ones. The purpose of our review is to report the most recent discoveries obtained by NGS studies for ALL diagnosis, risk stratification, and treatment planning. We also report the first efforts at NGS use for minimal residual disease (MRD) assessment, and early studies on the application of third generation sequencing in cancer research. Lastly, we consider the need for the integration of NGS analyses in clinical practice for genomic patients profiling from the personalized medicine perspective.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4542-4542
Author(s):  
Sule Unal ◽  
Gonul Hicsonmez ◽  
Sevgi Yetgin ◽  
Aytemiz Gurgey ◽  
Fatma Gumruk ◽  
...  

Abstract Leukemia constitutes 25–30% of all pediatric malignancy cases. The epidemiologic and demographic characteristics of this group of patients are important not only for determination of the prognostic factors, but also the risk factors. In this study, 683 patients under 16 years of age who were diagnosed with acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) between January 1980-July 2003 in Hacettepe University, Pediatric Hematolgy Division are analyzed retrospectively. Besides the epidemiologic characteristics including age, sex, geographic distiribution; the type of disease, clinical presentation, physical examination and laboratory findings on admission and the survival and prognosis relationships are also evaluated in order to determine the disease properties of our country. ALL patients have recieved St. Jude Total XI until 1997, and after 1997 they are treated by St. Jude Total XIII protocol. AML patients have been treated by AML 1995 and AML 1998 protocols. The study group includes 548 (80.2%) ALL and 135 (19.8%) AML cases. Two thirds of the all acute leukemia cases are males in both ALL and AML cases. The median age at diagnosis is 62 months for ALL and 108 months for AML patients. ALL is more common among 1–5 year old group; AML is more common among adolescent age group. The incidence of hematologic malignancies increases suddenly in 1997 and 1998 and then showes a decline later. The hematologic malignancy cases who have been admitted to our clinic is most commonly living in the northern and southeastern parts of Turkey. 50% of ALL and AML patients presents with the complaints of fever and pallor. Bone pain is significantly more common in ALL patients. Median time between onset of syptoms and diagnosis is 30 days for both ALL and AML patients. Lymphadenopathy is present in almost half of ALL and AML patients at diagnosis. Hepatomegaly (72.4% vs 50.4%) and splenomegaly (53.8% vs 36.3%) are more commonly observed in ALL then AML patients (p<0.001). The central nervous system (CNS) involvement is present in 5.8% of ALL and 5.9% of AML patients. There is no statisticaly significant difference between ALL and AML patients in terms of bone, mediastinial and CNS involvements. The most common cytogenetical abnormality in ALL patients is hypodiploidy. 25.4% of ALL and 43.7% of AML patients have relapsed subsequently. The most common type of relaps is seen in bone marrow in both ALL and AML cases, however CNS relaps is seen more commonly among ALL patients (31% vs 4%). Fatality rates of ALL and AML are 20.1% and 56.3%, respectively. The fatality rate of AML is significantly higher than ALL. The CNS involvement at diagnosis and sex have no influnce on the fatality rates; on the other hand the presence of relaps for ALL and AML groups and L3 subtype, being less then 1 year old at diagnosis for ALL cases have a negative effect on fatality rates. Also the fatality rates of ALL patients who have been diagnosed before 1997 and recieved St. Jude Total XI protocol has higher fatality rates then who have been diagnosed after 1997 and recieved St. Jude Total XIII (23.3% vs 14.1%). The collection of the cancer data throughout the country is crucial for the determination of the distribution and risk factors of our country. The best way of cancer data collection is development of cancer recording systems and analyzing these data for the determination of distribution and risk factors of patients with hematologic malignancies.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2126-2126
Author(s):  
Claudia D. Baldus ◽  
Cornelia Schlee ◽  
Julia Thibaut ◽  
Sandra Heesch ◽  
Arend Bohne ◽  
...  

Abstract The oncogenic ETS transcription factor ERG is involved in various cellular pathways including developmental regulation, proliferation, and differentiation. In hematopoiesis ERG plays a specific role during normal T-cell differentiation showing high expression levels in stem cells and down regulation in the progenitor compartment. In this regard, it is intriguing that aberrant expression of ERG was found in a subset of patients with acute T-lymphoblastic leukemia (T-ALL) and was associated with an inferior outcome. Furthermore, high level ERG expression was of adverse prognostic significance in patients with newly diagnosed acute myeloid leukemia (AML), thus highlighting ERG’s potential role in myeloid as well as T-lineage leukemogenesis. ERG3 (NM_182918) and ERG2 (NM_004449) represent the main isoforms and show abundant expression in myeloid and lymphoid hematopoietic progenitor cells. The expression pattern of specific ERG isoforms in acute leukemias has yet to be investigated. To further elucidate the nature of aberrant ERG expression we have determined the existence and transcriptional regulation of ERG isoforms in pretreatment bone marrow samples of adult T-ALL (n=21) and AML (n=20) patients as well as in normal CD34+ hematopoietic cells of healthy volunteers (n=5). 5′RACE revealed the presence of a new ERG isoform (ERG3Δex12) characterized by expression of exon 5 and absence of exon 12. Expression of ERG3Δex12 was verified by RT-PCR in AML, T-ALL, and CD34+ cells. In addition, real-time RT-PCR showed concomitant expression of the two main isoforms ERG2 and ERG3 in AML and normal CD34+ cells. In contrast, T-ALL patients lacked expression of ERG isoforms harboring exon 4 (ERG2). Promoter analyses of ERG2 and ERG3 revealed the presence of two CpG islands in the ERG2 promoter region, whereas no CpG island was predicted in the ERG3 promoter. Bisulfit conversion of genomic DNA and sequencing of cloned PCR products revealed a significantly higher degree of methylation of CpG island 2 in T-ALL samples (median: 86.4%, range: 16.0 – 98.8%) as compared to AML (median: 38.1%, range: 10.9 – 60.7%; P-value=0.0002 - two sided T-test). As for CpG island 1, CD34+ cells had the lowest rate of methylation in CpG island 2 (median: 7.7%, range: 2.4 – 20.7%). Thus, the differential expression of ERG isoforms is mediated by epigenetic silencing of exon 4 containing transcripts in T-ALL. In conclusion, the identification of the new ERG isoform (ERG3Δex12) suggests the association with different partners as the central exons, including exon 12, guide the interaction with different proteins. Furthermore, the distinct expression of specific ERG transcripts controlled by methylation adds to the complexity of ERG directed downstream pathways in different leukemic subtypes.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 877-877
Author(s):  
Dianne Pulte ◽  
Adam Gondos ◽  
Hermann Brenner

Abstract Background: There are few population based studies of long-term survival of adolescents and young adults (AYA) with hematologic malignancies, mostly pertaining to patients diagnosed in the 1990s or earlier. Traditionally, survival in AYA with hematologic malignancies has been worse than survival for children with similar malignancies. Here, we use period analysis to obtain up-to-date information on survival expectations of AYA diagnosed with hematologic malignancies through the early 21st century. Methods: Period analysis was used to calculate 5- and 10-year relative survival for AYA aged 15–24 diagnosed with hematologic malignancies for five calendar periods from 1981–85 to 2001–2005, using data from the Surveillance, Epidemiology, and End Results (SEER) database. Results: Data from 9836 patients aged 15–24 included in the SEER database who were diagnosed with Hodgkin’s lymphoma (HL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), and chronic myelocytic leukemia (CML) were analyzed. HL was the most common malignancy, accounting for about 50% of all hematologic maligancies in each calendar period examined. Survival strongly improved for each of the five hematologic malignancies. Increases in 10-year relative survival were as follows: HL, from 80.4 to 93.4%; NHL, from 55.6 to 76.2%; ALL, from 30.5 to 52.1%; AML, from 15.2 to 45.1%; CML, from 0 to 74.5% (p<0.0001 in all cases, see table). However, while survival improved steadily throughout the period examined for the lymphomas and CML, survival was stable during the late 1990s and early 21st century for the acute leukemias. Survival has not improved for AML since 1990–95 or for ALL since 1996–2000 (see table). Discussion: Survival expectations for AYA with hematologic malignancies have strongly improved since the 1980s. However, with the exception of HL, survival rates have not reached the levels observed for children diagnosed with the same malignancies. In particular, 10-year survival in children aged 10–14 with ALL was over 75% for the 2000–04 period1 compared to about 50% for AYA in 2001–05. Similarly, 10-year survival for children aged 0–14 diagnosed with acute non-lymphoblastic leukemia was about 60% in the 2000–04 period compared with less than 50% for AYA with AML in the 2001–05 period. Some caution must be used when comparing survival in AYA versus in children since survival estimates for children are for absolute survival, while those for AYA are for relative survival. However, relative survival in children and AYA is close to 100%, making the comparison relatively straightforward. Furthermore, survival estimates for the acute leukemias have not improved since the 1990s while survival for children continued to improve during the early 21st century. Reasons for the poorer survival observed may include differences in the biology of the malignancies, poorer compliance in AYA, differences in treatment protocols in children versus AYA, lower availability of clinical trials in AYA than in children, and low rates of health insurance in AYA patients, particularly after age 18. Further examination of the reasons for the poorer outcomes observed for AYA with acute leukemias may clarify this issue. 1 Pulte D, Gondos A, Brenner H. Trends in 5- and 10-year survival after diagnosis with childhood hematologic malignancies in the United States, 1990–2004. Accepted JNCI 7/08. Table: 10-year relative survival 1981–85 to 2001–05 by hematologic malignancy Diagnosis 1981– 85 1986–90 1991–95 1996–2000 2001–05 Diff1 p-val2 PE3 SE4 PE SE PE SE PE SE PE SE 1 Difference in survival, 1981–85 versus 2001–05. 2 P-value for trend. 3 Point estimate 4 Standard error HL 80.4 1.5 82.6 1.4 86.9 1.2 88.9 1.2 93.4 1.0 +13.0 <0.0001 NHL 55.6 3.1 59.9 2.9 62.7 2.7 67.9 2.6 76.2 2.3 +20.6 <0.0001 ALL 30.5 4.1 35.8 4.0 42.1 3.9 51.6 3.9 52.1 3.7 +21.6 <0.0001 AML 15.2 3.4 22.3 4.1 43.6 4.7 39.5 4.0 45.1 4.0 +29.9 <0.0001 CML 0 0 22.5 6.5 20.8 6.5 41.4 7.9 74.5 7.6 +74.5 <0.0001


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3889-3889
Author(s):  
Fortunato Morabito ◽  
Giovanna Cutrona ◽  
Anna Grazia Recchia ◽  
Sonia Fabris ◽  
Serena Matis ◽  
...  

Abstract Abstract 3889 Inflammatory cytokines play a biological role in the pathogenesis of Chronic lymphocytic leukemia (CLL). IL23 is a pro-inflammatory cytokine involved in T-cell responses and in tissue remodeling. It has been shown that the IL23 receptor (IL23R) is up-regulated in primary acute lymphoblastic leukemia (ALL) cells, and that IL23 inhibits ALL cell growth. Nevertheless, the anti-tumor function of IL23 still remains controversial. The role of the IL23R/IL23 axis in CLL has not been investigated so far. Herein we evaluated the expression pattern of IL23R/IL23 axis and its correlation with progression free survival (PFS) in CLL patients. A total of 233 newly diagnosed Binet stage A CLL cases from Italian institutions (clinicaltrials.gov NCT00917540) were studied for IL23R expression by flow-cytometry (FC) (median percentage IL23R expression=22.7, range 1.2–91.1). The median follow-up was 23 months (range 1–47). PFS information was obtained in 203 patients. Using the median value of 23% of IL23R as threshold, 8/102 IL23Rneg and 23/101 IL23Rpos CLL cases progressed with therapy requirement. The 2-year PFS probability of IL23Rneg patients was 89.7% as compared to 80.7% of IL23Rpos cases [χ2 7.7, P=.006; HR=3.0, 95%CI (1.3–6.6)]. Cases were then stratified according to IL23R positivity [IL23Rneg (102 cases) versus IL23Rpos (101 cases)]. No significant difference in terms of CD38 and ZAP-70 positive cases was observed, however, the IGVH mutational status could distinguish the two groups: IGHV-mutated in 92 (78.6%) of IL23Rneg vs 70 (61.9%) IL23Rpos and IGHV-unmutated in 25 (21.4%) vs 43 (38.1%), p=.006]. FISH analysis showed that IL23Rneg and IL23Rpos cases carrying 13q14.3 were respectively 53 (51.4%) and 44 (42.7%), while the number of patients with trisomy 12 were 8 and 10 respectively in cases with low and high IL23R expression. Deletion of 11q was detected in 3.9% (4/103) of IL23Rneg and in 8.7% (9/103) of IL23Rpos cases. Only 3 cases with 17p deletion were seen in this cohort of early CLL patients and all belonged to the IL23Rpos group. Overall, no significant differences in the incidence of the major genetic lesions were observed between the two groups. Il23R expression still remained independently associated with PFS also in multivariate analysis. In situ expression analysis of IL23R and of its ligand IL23 was then performed by immunohistochemistry (IHC) in 16 CLL samples [10 lymph node (LN) and 6 bone marrow (BM) biopsies] collected on diagnosis and in 8 control biopsies (4 lymph nodes with reactive follicular hyperplasia and 4 normal BM biopsies). IL23R was variably expressed in CLL and significantly expressed in the neoplastic clones of 9 (6 lymph nodes and 3 BM biopsies) of the 16 cases tested; IL23R was diffusely present along the membrane and cytoplasm of neoplastic cells effacing the lymph node or BM architecture (Fig. 1, upper-left). In CLL cases with low IL23R expression, IL23R was detected in few scattered lymphoid cells intermingling with neoplastic lymphocytes (Fig. 1, upper-right). IL23 was also detected, with a variable staining intensity (Fig. 1, middle-left), paralleling in part that of IL23R. Double-marker analysis confirmed the concomitant expression of IL23 and IL23R in CLL neoplastic infiltrates highlighting the co-localization of the two markers (Fig.1 middle-right) and suggesting the possibility of an autocrine IL23/IL23R loop in CLL clones. We speculated that the microenvironment of CLL cases rich in IL23R and IL23 could be enriched in IL17-producing cells. The IHC expression of IL17 in CLL cases with low or high IL23R and IL23 expression showed that CLL cases rich in IL23Rpos cells, also characterized by high IL23 expression, displayed significantly higher numbers of IL17pos infiltrating cells (Fig. 1 bottom-left), as compared with CLL cases with no or low expression of IL23R or IL23 (Fig. 1 bottom-right). In conclusion, our study shows that high IL23R expression predicts a worse PFS. Furthermore, we linked this picture with, the in situ engendering of a clone-related microenvironment characterized by the preponderancy of pro-inflammatory signals such as those of the IL23/IL23R/IL17 axis, and its correlates in the peripheral blood (i.e. IL23R expression on circulating CLL cells), may endorse its strong prognostic significance. This analysis prompts further investigation into the specific function of the IL23/IL23R/IL17 axis and its targets in the context of CLL. Figure 1. Figure 1. Disclosures: No relevant conflicts of interest to declare.


2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7074-7074
Author(s):  
K. D. Vu ◽  
V. R. Lavis ◽  
S. Strom ◽  
S. H. Faderl ◽  
M. Konopleva ◽  
...  

7074 Increasing evidence suggests associations between obesity, diabetes and/or hyperglycemia (DM/HG) and solid tumors. Less is known about the relationship of these metabolic factors to the hematologic malignancies. To determine the prevalence of DM/HG and obesity in pts with ALL and whether these are predictors of response and survival, we conducted a retrospective chart review of 299 pts with newly diagnosed ALL, who were evaluated at our institution between November 1999 and May 2005 and received hyper-CVAD therapy: fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and high-dose cytarabine. Median age was 43 yrs (range 15–83). Sixty-one percent of pts were male, and 39% female. Seventy-four percent had a diagnosis (dx) of precursor B cell ALL (22% Ph+), 18% Burkitt's ALL, 6% lymphoblastic lymphoma, 2% other. Prior to therapy, the overall prevalence of DM/HG (diabetes based on reported dx prior to ALL-dx, and hyperglycemia based on baseline serum glucose ≥200 mg/dL) was 16%. Pts with DM/HG were significantly older than those without DM/HG (median age 57 yrs vs. 40 yrs, p<0.001). Complete remission (CR) rate and the CR duration (CRD) were similar in the DM/HG vs. non-DM/HG group. However, the mean CRD was 80 wks in the HG separately group and 121 wks in the non-HG group (p=0.04). The mean CRD was 102 wks in the obese pts and 124 wks in the non-obese pts (p=.04). In univariate analysis, DM/HG, obesity, and older age were associated with shorter overall survival (OS). Mean OS of pts with DM/HG was 134 vs. 194 wks for pts without DM/HG, (p=0.2). Mean OS of obese pts was 136 vs. 199 wks for non-obese pts, (p=0.01). In a multivariable Cox regression model, the only factors that remained significant for survival were age, obesity, and white blood cell count (WBC). There was no significant difference in OS by leukemia diagnosis. In conclusion, the prevalence data suggests that DM/HG may be involved in the development of ALL. However, DM/HG has no impact on survival, probably because of its strong correlation with age. The association of obesity with shorter OS warrants further investigation. No significant financial relationships to disclose.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1449-1449
Author(s):  
Alexander Popov ◽  
Tatiana Verzhbitskaya ◽  
Grigory Tsaur ◽  
Alexander Tomilov ◽  
Olga Khlebnikova ◽  
...  

Abstract Abstract 1449 Central nervous system (CNS) involvement is one of the important risk factors in childhood acute leukemia (AL). Tumor cells detection in cerebrospinal fluid (CSF) is one of the main signs of CNS lesion. Traditionally blasts presence in CSF is assessed by conventional cytomorphology (CM) of cytospin slides. However, sensitivity of this method is relatively low. Flow cytometry (FC) having a higher sensitivity could provide better diagnostic applicability for CSF blasts detection. Aim. To compare results of tumor cells detection in CSF of children with AL by flow FC and CM. Methods. 183 samples from 52 boys and 31 girls aged from 5 months to 15 years with different types of acute lymphoblastic leukemia (ALL) (77 patients), acute myeloid leukemia (AML) (5 patients) and acute biphenotypic leukemia (1 patient) were investigated. 17 positive samples obtained by traumatic lumbar puncture were excluded from analysis because tumor blasts were also detected in peripheral blood. Comparison between FC and CM data was performed in 166 samples. Among these samples 61 was taken at the time of initial diagnostics, 34 – during AL follow-up, 17 – at relapse and 54 – during relapse monitoring. Monoclonal antibodies panels were constructed according to immunophenotype of tumor cells in bone marrow. Results. In 24 out of 166 samples (14.5%) tumor cells were detected by CM. In all these cases blasts were also found by FC, while FC allowed finding blasts in other 35 samples. Thus the total number of FC-positive samples was 59 out of 166 (35.5%). This frequency was significantly higher than rate of CM-positive cases (g < 0.0001). Among initial diagnostics samples there were 20 FC-positive and only 10 CM-positive patients (32.8% vs. 16.1%, p=0.0585). At relapse 9 (52.9%) patients were FC-positive, while 6 (35.3%) were CM-positive (p=0.4897). In both B-lineage and T-lineage ALL, analyzed separately, FC detected blasts in CSF frequently than CM (p=0.0098 and p=0.0002 respectively). Absolute blast count in 1 ml in CSF samples, positive by both methods was significantly higher than in samples, positive only by FC (median = 418, range 8–158171 and median = 34, range 5–2762 respectively, g = 0.0002). Thus FC allows detecting tumor cells in CSF much more frequently than conventional CM, which could be explained mainly by higher FC sensitivity. Moreover FC is applicable also for qualitative and quantitative monitoring of CNS lesion. Nevertheless prognostic impact of FC CSF investigation is questionable. Among 13 patients in whom discordant results were obtained in initial diagnostics samples and at relapse, only for one patient risk stratification could have been changed. For all other patients there were other risk factors, that decreased significance of FC leukemic blast detection in CSF. Conclusion. Flow cytometry allows more frequent detection of tumor blasts in CSF of children with AL, while prognostic significance of these findings is still unclear and needs to be confirmed in large prospective trials. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2013 ◽  
Vol 121 (21) ◽  
pp. 4265-4270 ◽  
Author(s):  
Kai Ling Liang ◽  
Loveena Rishi ◽  
Karen Keeshan

Abstract There is growing research interest in the mammalian Tribbles (Trib) family of serine/threonine pseudokinases and their oncogenic association with acute leukemias. This review is to understand the role of Trib genes in hematopoietic malignancies and their potential as targets for novel therapeutic strategies in acute myeloid leukemia and acute lymphoblastic leukemia. We discuss the role of Tribs as central signaling mediators in different subtypes of acute leukemia and propose that inhibition of dysregulated Trib signaling may be therapeutically beneficial.


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