STAT3 mutations in natural killer cells are associated with cytopenia in patients with chronic lymphoproliferative disorder of natural killer cells

Abstract Background Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is an extremely rare haematological disease. To the best of our knowledge, pulmonary infiltration in CLPD-NK has not been reported before. Our case study aimed to present the clinical characteristics, chest computed tomography (CT) findings, and flow cytometry immunophenotyping (FCI) results of an unusual case of migratory pulmonary infiltration in a patient with CLPD-NK. Case presentation A 51-year-old female patient was admitted to our hospital on October 8, 2019. Eight months before this visit, she had been diagnosed with pneumonia in a community hospital with 1 month of low-grade fever and had recovered after oral antibiotic administration. During follow-up, the patient presented with persistent peripheral blood (PB) lymphocytosis and ground-glass opacities on lung CT scans without any symptoms and signs or any evidence of infectious, allergic or autoimmunity pulmonary diseases. Abnormal NK cells were identified in the PB, bone marrow and bronchoalveolar lavage fluid (BALF) using FCI in our hospital. Eventually, the patient was diagnosed with pulmonary infiltration of CLPD-NK. The patient had an indolent clinical course without symptoms, hepatosplenomegaly or palpable lymphadenopathy and did not receive any therapy. The patient has remained in a good performance status 13 months after the diagnosis. Conclusions Our study described a unique case of pulmonary infiltration in a patient with CLPD-NK. The present case highlights the importance of FCI of the BALF in patients with lymphocytosis and pulmonary shadows to avoid misdiagnosis.

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A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

Blood Cancer Journal ◽

10.1038/s41408-020-0309-2 ◽

2020 ◽

Vol 10 (4) ◽

Author(s):

Vanessa Rebecca Gasparini ◽

Andrea Binatti ◽

Alessandro Coppe ◽

Antonella Teramo ◽

Cristina Vicenzetto ◽

...

Keyword(s):

Natural Killer Cells ◽

Natural Killer ◽

Lymphoproliferative Disorder ◽

Somatic Mutations ◽

High Definition ◽

Killer Cells

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Chronic Lymphoproliferative Disorder of Natural Killer Cells: A Rare Event

Cureus ◽

10.7759/cureus.10353 ◽

2020 ◽

Author(s):

Shafain Sheikh ◽

Sehreen Jahangir ◽

Samreen Khan ◽

Imran Ahmed

Keyword(s):

Natural Killer Cells ◽

Natural Killer ◽

Lymphoproliferative Disorder ◽

Rare Event ◽

Killer Cells

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Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3

Blood ◽

10.1182/blood-2014-04-570101 ◽

2015 ◽

Vol 125 (4) ◽

pp. 639-648 ◽

Cited By ~ 124

Author(s):

Emma M. Haapaniemi ◽

Meri Kaustio ◽

Hanna L. M. Rajala ◽

Arjan J. van Adrichem ◽

Leena Kainulainen ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Natural Killer Cells ◽

Natural Killer ◽

Mycobacterial Disease ◽

Killer Cells ◽

Activating Mutations ◽

Key Points ◽

Stat3 Mutations

Key Points Germline activating STAT3 mutations were detected in 3 patients with autoimmunity, hypogammaglobulinemia, and mycobacterial disease. T-cell lymphoproliferation, deficiency of regulatory and helper 17 T cells, natural killer cells, dendritic cells, and eosinophils were common.

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STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia

Blood ◽

10.1182/blood-2012-06-435297 ◽

2012 ◽

Vol 120 (15) ◽

pp. 3048-3057 ◽

Cited By ~ 222

Author(s):

Andres Jerez ◽

Michael J. Clemente ◽

Hideki Makishima ◽

Hanna Koskela ◽

Francis LeBlanc ◽

...

Keyword(s):

T Cell ◽

Natural Killer Cells ◽

Nk Cells ◽

Natural Killer ◽

Direct Sequencing ◽

Lymphoproliferative Disorders ◽

Wild Type ◽

Killer Cells ◽

Symptomatic Disease ◽

Stat3 Mutations

AbstractChronic lymphoproliferative disorders of natural killer cells (CLPD-NKs) and T-cell large granular lymphocytic leukemias (T-LGLs) are clonal lymphoproliferations arising from either natural killer cells or cytotoxic T lymphocytes (CTLs). We have investigated for distribution and functional significance of mutations in 50 CLPD-NKs and 120 T-LGL patients by direct sequencing, allele-specific PCR, and microarray analysis. STAT3 gene mutations are present in both T and NK diseases: approximately one-third of patients with each type of disorder convey these mutations. Mutations were found in exons 21 and 20, encoding the Src homology 2 domain. Patients with mutations are characterized by symptomatic disease (75%), history of multiple treatments, and a specific pattern of STAT3 activation and gene deregulation, including increased expression of genes activated by STAT3. Many of these features are also found in patients with wild-type STAT3, indicating that other mechanisms of STAT3 activation can be operative in these chronic lymphoproliferative disorders. Treatment with STAT3 inhibitors, both in wild-type and mutant cases, resulted in accelerated apoptosis. STAT3 mutations are frequent in large granular lymphocytes suggesting a similar molecular dysregulation in malignant chronic expansions of NK and CTL origin. STAT3 mutations may distinguish truly malignant lymphoproliferations involving T and NK cells from reactive expansions.

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A stab in the back: an unusual case of cutaneous neural infiltration as a manifestation of chronic lymphoproliferative disorder of natural killer cells

10.26226/morressier.5b4709836f4cb30010951c38 ◽

2018 ◽

Author(s):

Sarah Ní Mhaolcatha

Keyword(s):

Natural Killer Cells ◽

Natural Killer ◽

Lymphoproliferative Disorder ◽

Unusual Case ◽

Killer Cells

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Lack of Viral Load Within Chronic Lymphoproliferative Disorder of Natural Killer Cells: What Is Outside the Leukemic Clone?

Frontiers in Oncology ◽

10.3389/fonc.2020.613570 ◽

2021 ◽

Vol 10 ◽

Author(s):

Edoardo Giussani ◽

Andrea Binatti ◽

Giulia Calabretto ◽

Vanessa Rebecca Gasparini ◽

Antonella Teramo ◽

...

Keyword(s):

Natural Killer Cells ◽

Nk Cells ◽

Natural Killer ◽

Lymphoproliferative Disorder ◽

Cell Activation ◽

Nk Cell ◽

Sequencing Data ◽

Protein Antigens ◽

Killer Cells ◽

Leukemic Clone

Large granular lymphocyte leukemias (LGLL) are sustained by proliferating cytotoxic T cells or NK cells, as happens in Chronic Lymphoproliferative Disorder of Natural Killer cells (CLPD-NK), whose etiology is only partly understood. Different hypotheses have been proposed on the original events triggering NK cell hyperactivation and transformation, including a role of viral agents. In this perspective, we revise the lines of evidence that suggested a pathogenetic role in LGLL of the exposure to retroviruses and that identified Epstein Barr Virus (EBV) in other NK cell leukemias and lymphomas and focus on the contrasting data about the importance of viral agents in CLPD-NK. EBV was detected in aggressive NK leukemias but not in the indolent CLPD-NK, where seroreactivity against HTLV-1 retrovirus envelope BA21 protein antigens has been reported in patients, although lacking clear evidence of HTLV infection. We next present original results of whole exome sequencing data analysis that failed to identify viral sequences in CLPD-NK. We recently demonstrated that proliferating NK cells of patients harbor several somatic lesions likely contributing to sustain NK cell proliferation. Thus, we explore whether “neoantigens” similar to the BA21 antigen could be generated by aberrancies present in the leukemic clone. In light of the literature and new data, we evaluated the intriguing hypothesis that NK cell activation can be caused by retroviral agents located outside the hematopoietic compartment and on the possible mechanisms involved with the prospects of immunotherapy-based approaches to limit the growth of NK cells in CLPD-NK disease.

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