scholarly journals Insights on the Interplay between Cells Metabolism and Signaling: A Therapeutic Perspective in Pediatric Acute Leukemias

2020 ◽  
Vol 21 (17) ◽  
pp. 6251 ◽  
Author(s):  
Laura Anselmi ◽  
Salvatore Nicola Bertuccio ◽  
Annalisa Lonetti ◽  
Arcangelo Prete ◽  
Riccardo Masetti ◽  
...  

Nowadays, thanks to extensive studies and progress in precision medicine, pediatric leukemia has reached an extremely high overall survival rate. Nonetheless, a fraction of relapses and refractory cases is still present, which are frequently correlated with poor prognosis. Although several molecular features of these diseases are known, still the field of energy metabolism, which is widely studied in adult, has not been frequently explored in childhood leukemias. Metabolic reprogramming is a hallmark of cancer and is deeply connected with other genetic and signaling aberrations generally known to be key features of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). This review aims to clear the current knowledge on metabolic rewiring in pediatric ALL and AML, also highlighting the influence of the main signaling pathways and suggesting potential ideas to further exploit this field to discover new prognostic biomarkers and, above all, beneficial therapeutic options.

2021 ◽  
Vol 22 (16) ◽  
pp. 8738
Author(s):  
Ludovica Di Martino ◽  
Valeria Tosello ◽  
Edoardo Peroni ◽  
Erich Piovan

Acute leukemias, classified as acute myeloid leukemia and acute lymphoblastic leukemia, represent the most prevalent hematologic tumors in adolescent and young adults. In recent years, new challenges have emerged in order to improve the clinical effectiveness of therapies already in use and reduce their side effects. In particular, in this scenario, metabolic reprogramming plays a key role in tumorigenesis and prognosis, and it contributes to the treatment outcome of acute leukemia. This review summarizes the latest findings regarding the most relevant metabolic pathways contributing to the continuous growth, redox homeostasis, and drug resistance of leukemia cells. We describe the main metabolic deregulations in acute leukemia and evidence vulnerabilities that could be exploited for targeted therapy.


Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 139
Author(s):  
Kinga Panuciak ◽  
Mikołaj Margas ◽  
Karolina Makowska ◽  
Monika Lejman

Pediatric cancers predominantly constitute lymphomas and leukemias. Recently, our knowledge and awareness about genetic diversities, and their consequences in these diseases, have greatly expanded. Modern solutions are focused on mobilizing and impacting a patient’s immune system. Strategies to stimulate the immune system, to prime an antitumor response, are of intense interest. Amid those types of therapies are chimeric antigen receptor T (CAR-T) cells, bispecific antibodies, and antibody–drug conjugates (ADC), which have already been approved in the treatment of acute lymphoblastic leukemia (ALL)/acute myeloid leukemia (AML). In addition, immune checkpoint inhibitors (ICIs), the pattern recognition receptors (PRRs), i.e., NOD-like receptors (NLRs), Toll-like receptors (TLRs), and several kinds of therapy antibodies are well on their way to showing significant benefits for patients with these diseases. This review summarizes the current knowledge of modern methods used in selected pediatric malignancies and presents therapies that may hold promise for the future.


2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Elisa Dorantes-Acosta ◽  
Rosana Pelayo

Acute leukemias are the most common cancer in childhood and characterized by the uncontrolled production of hematopoietic precursor cells of the lymphoid or myeloid series within the bone marrow. Even when a relatively high efficiency of therapeutic agents has increased the overall survival rates in the last years, factors such as cell lineage switching and the rise of mixed lineages at relapses often change the prognosis of the illness. During lineage switching, conversions from lymphoblastic leukemia to myeloid leukemia, or vice versa, are recorded. The central mechanisms involved in these phenomena remain undefined, but recent studies suggest that lineage commitment of plastic hematopoietic progenitors may be multidirectional and reversible upon specific signals provided by both intrinsic and environmental cues. In this paper, we focus on the current knowledge about cell heterogeneity and the lineage switch resulting from leukemic cells plasticity. A number of hypothetical mechanisms that may inspire changes in cell fate decisions are highlighted. Understanding the plasticity of leukemia initiating cells might be fundamental to unravel the pathogenesis of lineage switch in acute leukemias and will illuminate the importance of a flexible hematopoietic development.


2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Philipp Makowka ◽  
Verena Stolp ◽  
Karoline Stoschek ◽  
Hubert Serve

Abstract Acute myeloid leukemia (AML) is a heterogeneous, highly malignant disease of the bone marrow. After decades of slow progress, recent years saw a surge of novel agents for its treatment. The most recent advancement is the registration of the Bcl-2 inhibitor ventoclax in combination with a hypomethylating agent (HMA) in the US and Europe for AML patients not eligible for intensive chemotherapy. Treatment of newly diagnosed AML patients with this combination results in remission rates that so far could only be achieved with intensive treatment. However, not all AML patients respond equally well, and some patients relapse early, while other patients experience longer periods of complete remission. A hallmark of AML is its remarkable genetic, molecular and clinical heterogeneity. Here, we review the current knowledge about molecular features of AML that help estimate the probability of response to venetoclax-containing therapies. In contrast to other newly developed AML therapies that target specific recurrent molecular alterations, it seems so far that responses are not specific for a certain subgroup. One exception is spliceosome mutations, where good response has been observed in clinical trials with venetoclax/azacitidine. These mutations are rather associated with a more unfavorable outcome with chemotherapy. In summary, venetoclax in combination with hypomethylating agents represents a significant novel option for AML patients with various molecular aberrations. Mechanisms of primary and secondary resistance seem to overlap with those towards chemotherapy.


2016 ◽  
Author(s):  
Richard A. Larson ◽  
Roland B Walter

The acute leukemias are malignant clonal disorders characterized by aberrant differentiation and proliferation of transformed hematopoietic progenitor cells. These cells accumulate within the bone marrow and lead to suppression of the production of normal blood cells, with resulting symptoms from varying degrees of anemia, neutropenia, and thrombocytopenia or from infiltration into tissues. They are currently classified by their presumed cell of origin, although the field is moving rapidly to genetic subclassification. This review covers epidemiology; etiology; classification of leukemia by morphology, immunophenotyping, and cytogenetic/molecular abnormalities; cytogenetics of acute leukemia; general principles of therapy; acute myeloid leukemia; acute lymphoblastic leukemia; and future possibilities. The figure shows the incidence of acute leukemias in the United States. Tables list World Health Organization (WHO) classification of acute myeloid leukemia and related neoplasms, expression of cell surface and cytoplasmic markers for the diagnosis of acute myeloid leukemia and mixed-phenotype acute leukemia, WHO classification of acute lymphoblastic leukemia, WHO classification of acute leukemias of ambiguous lineage, WHO classification of myelodysplastic syndromes, European LeukemiaNet cytogenetic and molecular genetic subsets in acute myeloid leukemia with prognostic importance, cytogenetic and molecular subtypes of acute lymphoblastic leukemia, terminology used in leukemia treatment, and treatment outcome for adults with acute leukemia. This review contains 1 highly rendered figure, 9 tables, and 117 references.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3786-3786
Author(s):  
Ting Liu ◽  
Dragana Jankovic ◽  
Laurent Brault ◽  
Sabine Ehret ◽  
Vincenzo Rossi ◽  
...  

Abstract Expression of meningioma 1 (MN1) has been proposed to be a negative prognostic marker in adult acute myeloid leukemia (AML). In pediatric leukemia, we found overexpression of MN1 in 53 of 88 cases: whereas no MN1 expression was detected in T-cell acute lymphoblastic leukemia (T-ALL), significant amounts of MN1 were found in immature B-cell ALL and most cases of infant leukemia. Interestingly, 17 of 19 cases harboring fusion genes involving the mixed-lineage leukemia (MLL-X) gene showed elevated MN1 expression. Lentiviral siRNA mediated MN1 knock-down resulted in cell cycle arrest and impaired clonogenic growth of 3 MLL-X-positive human leukemia cell lines overexpressing MN1 (THP-1, RS4;11, MOLM-13). In a mouse model of MLL-ENL-induced leukemia we found MN1 to be overexpressed as a consequence of provirus integration. Strikingly co-expression of MN1 with MLL-ENL resulted in significantly reduced latency for induction of an AML phenotype in mice suggesting functional cooperation. Immunophenotyping and secondary transplant experiments suggested that MN1 overexpression seems to expand the L-GMP cell population targeted by the MLL-ENL fusion. Gene expression profiling allowed defining a number of potential MN1 hematopoietic targets. Upregulation of CD34, FLT3, HLF, or DLK1 was validated in bone marrow transiently overexpressing MN1, in MN1-induced mouse acute myeloid leukemia, as well as in pediatric leukemias with elevated MN1 levels. Our work shows that MN1 is overexpressed in a significant fraction of pediatric acute leukemia, is essential for growth of leukemic cells, and that MN1 can act as a cooperating oncogene with MLL-ENL most probably through modification of a distinct gene expression program that leads to expansion of a leukemic progenitor population targeted by MLL-fusion genes.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3538-3538
Author(s):  
Adam Cohen ◽  
Lakshmanan Krishnamurti ◽  
Susan E. Creary

Abstract Abstract 3538 Introduction: Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer, accounting for approximately 3000 cases per year. Although the cure rate of pediatric ALL exceeds 80% in developing countries, treatment usually lasts 2.5–3.5 years and consists of a prolonged maintenance therapy phase. This phase consists is a 20 to 32 month regimen of daily oral 6-mercaptopurine (6MP), weekly oral methotrexate, monthly intravenous vincristine, and monthly oral steroid pulses. It is estimated that non-adherence rates range from 10–40%, which increase the risk of relapse and have a negative impact on disease free survival. Prior studies show that directly observed therapy (DOT) is the most effective way to improve medication adherence, and it is widely used in anti-tuberculosis and anti-retroviral therapy. DOT is defined as a strategy for ensuring patient compliance with therapy, where a healthcare worker watches the patient swallow each dose of a prescribed medication. While DOT may be a successful strategy for pediatric ALL, cost, inconvenience, perceived intrusiveness, and stigma relating to frequent visits by healthcare workers make it less viable strategy for pediatric ALL patients. A modified version of DOT utilizes existing cellular and computer technology (Mobile DOT) to view patients taking their medications over the internet without the need for custom hardware or programming. This technique is being studied in the pediatric sickle cell population, and preliminary results show adherence rates of ≥90%. The primary aim of this study is to see if Mobile DOT is a feasible and acceptable way to monitor pediatric ALL patients' 6MP adherence. Methods: This was a 30-day pilot study. ALL patients in their first remission were recruited if they were between 1–22 years of age, were in maintenance therapy for ≥1 month, and had daily access to a phone or computer capable of recording and submitting videos to Mobile DOT. We instructed participants how to submit the videos and they received daily reminders alerts as text messages and emails to take their medication. As adherence measures, we used direct observation and self-reported adherence using the Moriskey Medication Adherence Surveys (MMAS-4). The MMAS-4 is a validated adherence survey on a scale of 0–4, where lower scores indicate higher adherence. We measured Mobile DOT participant satisfaction with a 12 question Likert scale survey at the end of the study. Participants received a small monetary compensation for completing surveys and if they achieved ≥90% adherence for the 30 days. Results: We approached 20 prospective participants and 11 enrolled. Two subjects withdrew from the study; one was withdrawn because he was instructed to stop 6MP therapy due to myelosuppression and the other was withdrawn because his software was incompatible with our system. At enrollment, mean MMAS-4 score was 0.8 (SD ± 1.2, range 0–3), suggesting good overall adherence. By the end of study, MMAS-4 score trended toward improvement to 0.3 (SD ± 0.5, range: 0–1). Of the participants with moderate adherence (scores 2–3, n=3), all improved to good adherence (score 0–1) at the end of the study. Mean adherence measured with direct observation was 27.0/30 (SD ± 2.5 range 23–30) or 90.0% (SD ± 8.3% range 76–100%). Survey data shows that most patients (n=5) found Mobile DOT and the alerts to be helpful. Also, most participants (n=8) found that Mobile DOT took less than five minutes each day and did not invade privacy. All participants agreed that Mobile DOT was easy to use. Conclusions: This study suggests that Mobile DOT is a feasible way to monitor medication adherence in pediatric ALL patients. In addition, we found pediatric ALL patients had high adherence rates and most found Mobile DOT to be acceptable. These results suggest that Mobile DOT may be an effective strategy to ensure adequate 6MP medication adherence in pediatric ALL throughout maintenance therapy. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 940-947 ◽  
Author(s):  
Stefan Faderl ◽  
Varsha Gandhi ◽  
Susan O'Brien ◽  
Peter Bonate ◽  
Jorge Cortes ◽  
...  

AbstractClofarabine (2-chloro-2′-fluoro-deoxy-9-β-D-arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine (ara-C). We conducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leukemia [AML], 2 acute lymphoblastic leukemia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myeloid leukemia (CML).1 Clofarabine was given as a 1-hour intravenous infusion for 5 days (days 2 through 6) followed 4 hours later by ara-C at 1 g/m2 per day as a 2-hour intravenous infusion for 5 days (days 1 through 5). The phase 2 dose of clofarabine was 40 mg/m2 per day for 5 days. Among all patients, 7 (22%) achieved complete remission (CR), and 5 (16%) achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 38%. No responses occurred in 3 patients with ALL and CML. One patient (3%) died during induction. Adverse events were mainly less than or equal to grade 2, including transient liver test abnormalities, nausea/vomiting, diarrhea, skin rashes, mucositis, and palmoplantar erythrodysesthesias. Plasma clofarabine levels generated clofarabine triphosphate accumulation, which resulted in an increase in ara-CTP in the leukemic blasts. The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy.


2007 ◽  
Vol 25 (31) ◽  
pp. 4922-4928 ◽  
Author(s):  
Terzah M. Horton ◽  
Patrick A. Thompson ◽  
Stacey L. Berg ◽  
Peter C. Adamson ◽  
Ashish M. Ingle ◽  
...  

Purpose To determine the tolerability, pharmacokinetics, and mechanisms of temozolomide resistance in children with relapsed or refractory leukemia. Patients and Methods Cohorts of three to six patients received 200 or 260 mg/m2/d of temozolomide by mouth daily for 5 days every 28 days. Toxicities, clinical response, and pharmacokinetics were evaluated. Pretreatment leukemia cell O6-methylguanine–DNA methyltransferase (MGMT) activity, tumor and plasma MGMT promoter methylation, and microsatellite instability (MSI) were examined in 14 of 16 study patients and in tissue bank samples from children with acute leukemia not treated with temozolomide (MGMT, n = 67; MSI, n = 65). Results Sixteen patients (nine female, seven male; acute lymphoblastic leukemia [ALL], n = 8; acute myeloid leukemia [AML], n = 8), median age 11 years (range, 1 to 19 years), received either 200 mg/m2/d (nine enrolled, three assessable for toxicity) or 260 mg/m2/d (seven enrolled, three assessable for toxicity) of temozolomide. Temozolomide was well tolerated and no dose-limiting toxicities occurred. The mean clearance of temozolomide was 107 mL/min/m2, with a volume of distribution of 20 L/m2 and half-life of 109 minutes. MGMT activity in leukemia cells was quite variable and was highest in patients with relapsed ALL. Only one patient had MSI. Two patients had a partial response. Both of these patients had no detectable MGMT activity; both also had methylated MGMT promoters and were MSI stable. Conclusion Temozolomide was well tolerated at doses as high as 260 mg/m2/d for 5 days in children with relapsed or refractory leukemia. Increased MGMT activity may account for the temozolomide resistance in children with relapsed leukemia. Leukemia cell MGMT activity was higher in pediatric ALL than AML (P < .0001).


2021 ◽  
Vol 11 ◽  
Author(s):  
Gabriele Merati ◽  
Marianna Rossi ◽  
Anna Gallì ◽  
Elisa Roncoroni ◽  
Silvia Zibellini ◽  
...  

Acute leukemia of ambiguous lineage (ALAL) is a rare type of leukemia and represents an unmet clinical need. In fact, due to heterogeneity, substantial rarity and absence of clinical trials, there are no therapeutic guidelines available. We investigated the genetic basis of 10 cases of ALAL diagnosed at our centre from 2008 and 2020, through a targeted myeloid and lymphoid sequencing approach. We show that this rare group of acute leukemias is enriched in myeloid-gene mutations. In particular we found that RUNX1 mutations, which have been found double mutated in 40% of patients and tend to involve both alleles, are associated with an undifferentiated phenotype and with lineage ambiguity. Furthermore, because this feature is typical of acute myeloid leukemia with minimal differentiation, we believe that our data strengthen the idea that acute leukemia with ambiguous lineage, especially those with an undifferentiated phenotype, might be genetically more closer to acute myeloid leukemia rather than acute lymphoblastic leukemia. These data enrich the knowledge on the genetic basis of ALAL and could have clinical implications as an acute myeloid leukemia (AML) – oriented chemotherapeutic approach might be more appropriate.


Sign in / Sign up

Export Citation Format

Share Document