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Background/Aim: Hairy cell leukemia (HCL) is a well-known lymphoproliferative disease with very effective treatment approaches primarily relying on purine analogues. However, these treatments are associated with profound and prolonged immunosuppression. Merkel cell carcinoma (MCC) is a rare and extremely aggressive skin tumor with an increased incidence in immunocompromised patients. Case Report: We report a case of a patient with HCL who was diagnosed with MCC, while in remission following retreatment with pentostatin, which induced a profound decrease in CD4 (+) T-cells. Conclusion: Our case provides further evidence supporting the hypothesis of a significant association between immunosuppression and MCC pathogenesis. [ABSTRACT FROM AUTHOR]

The analysis of hydrogen deuterium exchange by mass spectrometry as a function of temperature and mutation has emerged as a generic and efficient tool for the spatial resolution of protein networks that are proposed to function in the thermal activation of catalysis. In this work, we extend temperature-dependent hydrogen deuterium exchange from apo-enzyme structures to protein-ligand complexes. Using adenosine deaminase as a prototype, we compared the impacts of a substrate analog (1-deaza-adenosine) and a very tight-binding inhibitor/transition state analog (pentostatin) at single and multiple temperatures. At a single temperature, we observed different hydrogen deuterium exchange-mass spectrometry properties for the two ligands, as expected from their 106-fold differences in strength of binding. By contrast, analogous patterns for temperature-dependent hydrogen deuterium exchange mass spectrometry emerge in the presence of both 1-deaza-adenosine and pentostatin, indicating similar impacts of either ligand on the enthalpic barriers for local protein unfolding. We extended temperature-dependent hydrogen deuterium exchange to a function-altering mutant of adenosine deaminase in the presence of pentostatin and revealed a protein thermal network that is highly similar to that previously reported for the apo-enzyme (Gao et al., 2020, JACS 142, 19936-19949). Finally, we discuss the differential impacts of pentostatin binding on overall protein flexibility versus site-specific thermal transfer pathways in the context of models for substrate-induced changes to a distributed protein conformational landscape that act in synergy with embedded protein thermal networks to achieve efficient catalysis.

T-prolymphocytic leukemia (T-PLL) is a rare malignancy of mature T-cells with distinct clinical, cytomorphological, and molecular genetic features. The disease typically presents at an advanced stage, with marked leukocytosis, B symptoms, hepatosplenomegaly, and bone marrow failure. It usually follows an aggressive course from presentation, and the prognosis is often considered dismal; the median overall survival is less than one year with conventional chemotherapy. This case report describes a patient with T-PLL who, after an unusually protracted inactive phase, ultimately progressed to a highly invasive, organ-involving disease. After initial treatments failed, a novel treatment approach resulted in a significant response.

T-prolymphocytic leukemia (T-PLL) is a rare malignancy of mature T-cells with distinct clinical, cytomorphological, and molecular genetic features. The disease typically presents at an advanced stage, with marked leukocytosis, B symptoms, hepatosplenomegaly, and bone marrow failure. It usually follows an aggressive course from presentation, and the prognosis is often considered dismal; the median overall survival is less than one year with conventional chemotherapy. This case report describes a patient with T-PLL who, after an unusually protracted inactive phase, ultimately progressed to a highly invasive, organ-involving disease. After initial treatments failed, a novel treatment approach resulted in a significant response. [ABSTRACT FROM AUTHOR]

Purpose of Review: This article summarizes the current state of knowledge of hairy cell leukemia (HCL) regarding presentation, diagnosis, therapy, and monitoring, including perspectives on emergent therapies. Recent Findings: Over the past decade, there has been enormous progress in the understanding of the biology of HCL which has led to the development of novel therapeutic strategies. The maturation of data regarding existing management strategies has also lent considerable insight into therapeutic outcomes and prognosis of patients treated with chemo- or chemoimmunotherapy. Purine nucleoside analogs remain the cornerstone of treatment, and the addition of rituximab has deepened and prolonged responses in the upfront and relapsed setting. Targeted therapies now have a more defined role in the management of HCL, with BRAF inhibitors now having a potential in the first-line setting in selected cases as well as in relapse. Next-generation sequencing for the identification of targetable mutations, evaluation of measurable residual disease, and risk stratification continue to be areas of active investigation. Summary: Recent advances in HCL have led to more effective therapeutics in the upfront and relapsed setting. Future efforts will focus on identifying patients with high-risk disease who require intensified regimens. Multicenter collaborations are the key to improving overall survival and quality of life in this rare disease. [ABSTRACT FROM AUTHOR]

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm that originates from mature post-thymic T-cells. Cutaneous manifestations are a common presentation in T-PLL but rarely are a presentation in the recurrent setting. Here, we describe the case of a 75-year-old female with a history of T-PLL—who at the time of initial diagnosis did not exhibit any rash—presenting with diffuse rash, facial swelling, sore throat, and dysphagia 7 months later and was found to have recurrent T-PLL. She had diffuse lymphadenopathy and diffuse skin lesions. Biopsy of the skin lesions also confirmed infiltration with T-PLL cells. After review of the literature, no previously reported cases of recurrent T-PLL presented as diffuse skin lesions. This case demonstrates that recurrent T-PLL may present with diffuse rash, respiratory distress, and anasarca. It is important to stay vigilant in patients with history of T-PLL to recognize signs of recurrent disease to allow prompt diagnosis and treatment. [ABSTRACT FROM AUTHOR]

The special structure of pentostatin causes it to possess a wide spectrum of biological and pharmacological properties, and it has been extensively employed to treat malignant tumors and is the first-line treatment for hairy cell leukemia. Pentostatin is mainly distributed in several actinomycetes and fungi species. However, its low titer in microbes is not able to meet medical needs. Here, we report a strain improvement strategy based on combined atmospheric and room-temperature plasma (ARTP) mutagenesis and ribosome engineering screening, as well as fermentation optimization, for enhanced pentostatin production. The original strain, Actinomadura sp. ATCC 39365, was treated with ARTP and screened by ribosome engineering to obtain one stable pentostatin high-yield mutant Actinomadura sp. S-15, which produced 86.35 mg/L pentostatin, representing a 33.79% increase compared to Actinomadura sp. ATCC 39365. qRT-PCR analysis revealed that pentostatin biosynthesis-related gene expression was significantly upregulated in Actinomadura sp. S-15. Then, to further enhance pentostatin production, the fermentation medium was optimized in flask culture and the pentostatin production of Actinomadura sp. S-15 reached 152.06 mg/L, which is the highest pentostatin production reported so far. These results demonstrate the effectiveness of combined ARTP mutation, ribosome engineering screening, and medium optimization for the enhancement of pentostatin production, and provide a methodology enabling the sustainable production of pentostatin on an industrial scale. [ABSTRACT FROM AUTHOR]

We report outcomes of 60 patients with steroid-refractory (SR)-aGVHD treated with pentostatin. Almost half (47%) of patients had grade 4 GVHD-22% had stage 3-4 liver GVHD and 51% had stage 3-4 lower gastrointestinal tract (LGI) GVHD. Patients received a median of 3 courses (range, 1-9) of pentostatin. Day 28 overall response rate (ORR) was 33% (n = 20) (complete response 18% (n = 11), partial response 15% (n = 9)). Non-relapse mortality was 72% (95% confidence interval (CI) 61-84%) and overall survival (OS) was 21% (95% CI 12-32%) at 18 months. On univariate analysis, age >60 years (HR 1.9, 95% CI 1.01-3.7, p = 0.045) and presence of liver GVHD (HR 1.9, 95% CI 1.9, 95% CI 1.5-3.3, p = 0.03) were significant predictors of poor OS while patients with LGI GVHD had superior OS than those without (HR 0.4, 95% CI 0.2-0.8, p = 0.01). On stratified analysis, patients

Pentostatin (PNT), a nucleoside antibiotic with a 1,3-diazo ring structure, is distributed in several actinomycetes and fungi species. Its special structure makes PNT possess a wide spectrum of biological and pharmacological properties, such as antibacterial, antitrypanosomal, anticancer, antiviral, herbicidal, insecticidal, and immunomodulatory effects. Because of the promising adenosine deaminase inhibitory activity of PNT, its extensive application in the clinical treatment of malignant tumors has been extensively studied. However, the fermentation level of microbial-derived PNT is low and cannot meet medical needs. Because the biosynthesis pathway of PNT is obscure, only high-yield mutant screening and optimization of medium components and fermentation processes have been conducted for enhancing its production. Recently, the biosynthesis pathways of PNT in actinomycetes and fungi hosts have been revealed successively, and the large-scale production of PNT by systematic metabolic engineering will become an inevitable trend. Therefore, this review covers all aspects of PNT research, in which major advances in understanding the resource microorganisms, mechanism of action, and biosynthesis pathway of PNT were achieved and diverse clinical applications of PNT were emphasized, and it will lay the foundation for commercial transformation and industrial technology of PNT based on systematic metabolic engineering. [ABSTRACT FROM AUTHOR]

The special structure of pentostatin causes it to possess a wide spectrum of biological and pharmacological properties, and it has been extensively employed to treat malignant tumors and is the first-line treatment for hairy cell leukemia. Pentostatin is mainly distributed in several actinomycetes and fungi species. However, its low titer in microbes is not able to meet medical needs. Here, we report a strain improvement strategy based on combined atmospheric and room-temperature plasma (ARTP) mutagenesis and ribosome engineering screening, as well as fermentation optimization, for enhanced pentostatin production. The original strain, Actinomadura sp. ATCC 39365, was treated with ARTP and screened by ribosome engineering to obtain one stable pentostatin high-yield mutant Actinomadura sp. S-15, which produced 86.35 mg/L pentostatin, representing a 33.79% increase compared to Actinomadura sp. ATCC 39365. qRT-PCR analysis revealed that pentostatin biosynthesis-related gene expression was significantly upregulated in Actinomadura sp. S-15. Then, to further enhance pentostatin production, the fermentation medium was optimized in flask culture and the pentostatin production of Actinomadura sp. S-15 reached 152.06 mg/L, which is the highest pentostatin production reported so far. These results demonstrate the effectiveness of combined ARTP mutation, ribosome engineering screening, and medium optimization for the enhancement of pentostatin production, and provide a methodology enabling the sustainable production of pentostatin on an industrial scale.

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Pentostatin (PNT), a nucleoside antibiotic with a 1,3-diazo ring structure, is distributed in several actinomycetes and fungi species. Its special structure makes PNT possess a wide spectrum of biological and pharmacological properties, such as antibacterial, antitrypanosomal, anticancer, antiviral, herbicidal, insecticidal, and immunomodulatory effects. Because of the promising adenosine deaminase inhibitory activity of PNT, its extensive application in the clinical treatment of malignant tumors has been extensively studied. However, the fermentation level of microbial-derived PNT is low and cannot meet medical needs. Because the biosynthesis pathway of PNT is obscure, only high-yield mutant screening and optimization of medium components and fermentation processes have been conducted for enhancing its production. Recently, the biosynthesis pathways of PNT in actinomycetes and fungi hosts have been revealed successively, and the large-scale production of PNT by systematic metabolic engineering will become an inevitable trend. Therefore, this review covers all aspects of PNT research, in which major advances in understanding the resource microorganisms, mechanism of action, and biosynthesis pathway of PNT were achieved and diverse clinical applications of PNT were emphasized, and it will lay the foundation for commercial transformation and industrial technology of PNT based on systematic metabolic engineering.

Coformycin and pentostatin are structurally related N-nucleoside inhibitors of adenosine deaminase characterized by an unusual 1, 3-diazepine nucleobase. Herein, the cof gene cluster responsible for coformycin biosynthesis is identified. Reconstitution of the coformycin biosynthetic pathway in vitro demonstrates that it overlaps significantly with the early stages of L-histidine biosynthesis. Committed entry into the coformycin pathway takes place via conversion of a shared branch point intermediate to 8-ketocoformycin-50-monophosphate catalyzed by CofB, which is a homolog of succinylaminoimidazolecarboxamide ribotide (SAICAR) synthetase. This reaction appears to proceed via a Dieckmann cyclization and a retro-aldol elimination, releasing ammonia and D-erythronate-4-phosphate as coproducts. Completion of coformycin biosynthesis involves reduction and dephosphorylation of the CofB product, with the former reaction being catalyzed by the NADPH-dependent dehydrogenase CofA. CofB also shows activation by adenosine triphosphate (ATP) despite the reaction requiring neither a phosphorylated nor an adenylated intermediate. This may serve to help regulate metabolic partitioning between the L-histidine and coformycin pathways. [ABSTRACT FROM AUTHOR]

Purpose of Review: To summarise diagnostic clinical/laboratory findings and highlight differences between classical hairy cell leukaemia (HCLc) and hairy cell leukaemia variant (HCLv). Discussion of prognosis and current treatment indications including novel therapies, linked to understanding of the underlying molecular pathogenesis. Recent Findings: Improved understanding of the underlying pathogenesis of HCLc, particularly the causative mutation BRAF V600E, leading to constitutive activation of the MEK/ERK signalling pathway and increased cell proliferation. Summary: HCLc is caused by BRAF V600E mutation in most cases. Purine nucleoside analogue (PNA) therapy is the mainstay of treatment, with the addition of rituximab, improving response and minimal residual disease (MRD) clearance. Despite excellent responses to PNAs, many patients will eventually relapse, requiring further therapy. Rarely, patients are refractory to PNA therapy. In relapsed/refractory patients, novel targeted therapies include BRAF inhibitors (BRAFi), anti-CD22 immunoconjugate moxetumomab and Bruton tyrosine kinase inhibitors (BTKi). HCLv has a worse prognosis with median overall survival (OS), only 7–9 years, despite the combination of PNA/rituximab improving front-line response. Moxetumomab or ibrutinib may be a viable treatment but lacks substantial evidence. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is an indolent B-cell malignancy, with long-term responses to purine analogs, but with decreasing efficacy and increasing toxicity with repeated courses. Leukemic cells express CD22, CD20, CD25, tartrate-resistant acid phosphatase (TRAP), annexin 1A (Anxa1), and BRAF V600E mutation. HCLv, lacking CD25, Anxa1, TRAP, and BRAF V600E, is more aggressive and less purine analog-sensitive. A molecularly defined IGHV4-34+ variant is also resistant whether HCL or HCLv immunophenotypically. Traces of HCL cells, termed minimal residual disease (MRD), accompany most with complete remission (CR) and may cause relapse. Rituximab has limited single-agent activity, but frequent CR without MRD when combined with purine analog, albeit with chemotherapy toxicities. The anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox can achieve MRD-negative CR in multiply relapsed HCL without chemotherapy toxicities and was FDA approved in 2018 as Lumoxiti. Investigational oral non-chemotherapy options also include Vemurafenib or Dabrafenib/Trametinib targeting BRAF V600E ± MEK, and Ibrutinib targeting Bruton's tyrosine kinase. [ABSTRACT FROM AUTHOR]