T-cell large granular lymphocyte leukemia and related disorders

T-cell large granular lymphocyte (LGL) leukemia is a clonal proliferation of cytotoxic T cells, which causes neutropenia, anemia, and/or thrombocytopenia. This condition is often associated with autoimmune disorders, especially rheumatoid arthritis, and other lymphoproliferative disorders. The diagnosis is suggested by flow cytometry demonstrating an expansion of CD8(+)CD57(+) T cells and is confirmed by T-cell receptor gene rearrangement studies. Mounting evidence suggests that LGL leukemia is a disorder of dysregulation of apoptosis through abnormalities in the Fas/Fas ligand pathway. In most patients, this is an indolent disorder, and significant improvement of cytopenias can be achieved with immunosuppressive agents such as steroids, methotrexate, cyclophosphamide, and cyclosporin A. This review provides a concise, up-to-date summary of LGL leukemia and the related, more aggressive, malignancies of cytotoxic T cells and natural killer cells.     

TCRgammadelta+ large granular lymphocyte leukemias reflect the spectrum of normal antigen-selected TCRgammadelta+ T-cells.

T-cell large granular lymphocytes (LGL) proliferations range from reactive expansions of activated T cells to T-cell leukemias and show variable clinical presentation and disease course. The vast majority of T-LGL proliferations express TCRalphabeta. Much less is known about the characteristics and pathogenesis of TCRgammadelta+ cases. We evaluated 44 patients with clonal TCRgammadelta+ T-LGL proliferations with respect to clinical data, immunophenotype and TCR gene rearrangement pattern. TCRgammadelta+ T-LGL leukemia patients had similar clinical presentations as TCRalphabeta+ T-LGL leukemia patients. Their course was indolent and 61% of patients were symptomatic. The most common clinical manifestations were chronic cytopenias - neutropenia (48%), anemia (23%), thrombocytopenia (9%), pancytopenia (2%) - and to a lesser extent splenomegaly (18%). Also multiple associated autoimmune (34%) and hematological (14%) disorders were found. Leukemic LGLs were predominantly positive for CD2, CD5, CD7, CD8, and CD57, whereas variable expression was seen for CD16, CD56, CD11b, and CD11c. The Vgamma9/Vdelta2 immunophenotype was found in 48% of cases and 43% of cases was positive for Vdelta1, reflecting the TCR-spectrum of normal TCRgammadelta+ T-cells in adult PB. Identification of the well-defined post-thymic Vdelta2-Jdelta1 selection determinant in all evaluable Vgamma9+/Vdelta2+ patients, is suggestive of common (super)antigen involvement in the pathogenesis of these TCRgammadelta+ T-LGL leukemia patients.     

Molecular Study of Parvovirus B19 Infection in Children with Acute Myeloid Leukemia

Background: Parvovirus B19 is a common viral infection in children. Nearby evidences are present about itsassociation with acute leukemia, especially acute lymphoblast leukemia. Nevertheless, scanty reports have discussedany role in acute myeloid leukemia (AML). Purpose: To evaluate the frequency of virological markers of B19 infectionincluding its DNA along with specific immunoglobulins G (IgG) and M (IgM) among children with newly diagnosedAML. Besides, describing the clinical importance of Parvovirus B19 infection in those patients. Patients and methods:A case-control retrospective study was conducted on 48 children recently diagnosed with AML before and duringchemotherapy induction and 60 healthy control. Specific serum IgM and IgG levels were determined by enzyme linkedimmunosorbant assay (ELISA) and DNA detection by polymerase chain reaction (PCR). Results: Parvovirus DNA wasdetected in 20 patients with AML. IgM was found in sera of four patients and one case had positive DNA and IgG (5%).Patients with recent parvovirus B19 infection had a significantly reduced hemoglobin levels, RBCs counts, plateletcounts, neutrophil counts and absolute lymphocytosis (p=0.01, p=0.0001, p=0.01, p=0.02, p=0.0003, respectively).There were no clinical findings with statistically significant association to recent infection. Half of the patients withAML had positive PCR and/or IgM for parvovirus B19. Among children with AML under chemotherapy, there werereduced hemoglobin levels (P=0.03), reduced platelet counts (P=0.0001) and absolute neutropenia (mean±SD, 1.200±1.00) in those with parvovirus B19 infection. More than half of patients with parvovirus B19 (72.2%) had positive PCRand/or IgM and 36.4% of them had positive IgG. Conclusion: This study highlights that parvovirus B19 is commonin children with AML either at diagnosis or under chemotherapy. There are no clinical manifestations that can be usedas markers for its presence, but hematological laboratory findings can provide evidence for infection in the presenceof anemia and neutropenia. Detection of parvovirus B19 by combined molecular and serological markers is requiredin such patients for accurate diagnosis.     

T-large granular lymphocyte leukemia accompanied by an increase of natural killer cells (CD3-) and associated with ulcerative colitis and autoimmune hepatitis

Clonal expansion of large granular lymphocyte(LGL) have been classified into T-LGL and NK-LGL leukemia. T-LGL leukemia cells have a CD3+ phenotype and show clonal T-cell receptor(TCR) gene rearrangement. NK-LGL leukemia cells have a CD3- phenotype and no TCR gene rearrangement. We report a case of T-LGL leukemia accompanied by NK LGL expansions in a 65-year-old man who was observed 3 years earlier to have a LGL lymphocytosis in association with ulcerative colitis(UC) and autoimmune hepatitis (AIH). Phenotypic analysis of peripheral blood by flow cytometry disclosed an increase of both T-LGL(CD3+,CD56-,CD57+,and TCRalphabeta+) and NK-LGL (CD3-,CD16+,CD56+, and CD57+). Clonal rearrangement of the TCR beta gene was detected. A diagnosis of UC and AIH was made on the basis of the X-ray and mucosal biopsy findings of the large intestine, and on the scoring system for diagnosis of AIH, respectively. The disease was nonprogressive, and mesalazine and prednisolone were successful for treatment of UC and AIH. Previously reported cases of T-LGL, NK-LGL leukemia, or NK cell lymphocytosis had no association with UC or AIH, and there have been no reports having both T-LGL leukemia with T-cell receptor gene rearrangement and chronic NK cell lymphocytosis co-existing in a single patient.     

Hematological remission and long term hematological control of acute myeloblastic leukemia induced and maintained by granulocyte-colony stimulating factor (G-CSF) therapy

We describe a case of a patient with CD34+, TdT+, CD13-, CD33-, MPO- undifferentiated acute leukemia who refused chemotherapy and who achieved complete hematological remission 14 months after the diagnosis, during a short course of granulocyte-colony stimulating factor (G-CSF) for neutropenia and life threatening infection. Relapse occurred approximately one year later and G-CSF was reintroduced, being maintained for 4 months, at a dose and frequency adapted to maintain normal blood counts, a complete hematological remission being achieved again. Five months after withdrawing the G-CSF therapy a second relapse was observed; G-CSF was tried again with success, resulting in a very good hematological response that was sustained by G-CSF maintenance therapy. One year latter there was the need of increasing the doses of G-CSF in order to obtain the same hematological effect, at same time blast cells acquired a more mature CD34+, TdT-, CD13+, CD33-, MPO+ myeloid phenotype. Finally, the patient developed progressive neutropenia, anemia, thrombocytopenia and acute leukemia in spite of G-CSF therapy, dying 64 months after initial diagnosis (50 months after starting G-CSF therapy) with overt G-CSF resistant acute myeloblastic leukemia (AML), after failure of conventional induction chemotherapy.     

A T chronic lymphocytic leukemia with large granular lymphocytes. Phenotype and functions of leukemic cells under in vitro treatment by differentiation inducers

We reported the morphologic, phenotypic and functional characteristics of leukemic cells with natural killer (NK) properties in a case of T chronic lymphocytic leukemia with large granular lymphocytes. These cells were cytologically and cytochemically characterized as phosphatase acid positive large granular lymphocytes (LGL), and presented parallel tubular arrays at the ultra structural level. They displayed a CD2, CD3, CD8, CD11, Leu 7, and Leu 11 positive phenotype while they lacked B cell markers including surface immunoglobulins. In addition, they expressed human leukocyte antigens (HLA) Class I, but no Class II antigens. These phenotypic studies were also performed after cells were cultured in vitro with 12-0-tetradecanoyl phorbol 13-acetate, gamma interferon, 5-azacytidine, sodium butyrate, phytohemagglutinin, and interleukin 2 (IL2). The cell surface markers underwent several significant changes. Among them we noted a higher percentage of labeled cells with anti-CD6 and CD7 monoclonal antibodies (moAbs), and a positivity with an anti-CD19 (B4) moAb. The leukemic LGL spontaneously developed a NK activity on K 562 tumor cells, which was not affected under the various T and B cells growth factors because they became more sensitive to IL2; but they were also stimulated by a 50-kilodalton (KD) B cell growth factor (BCGF) factor devoid of any T cell proliferation activity. Together these results gave a better characterization of azurophilic granules containing T chronic lymphocytic leukemia, and enabled the documentation of the differentiation of LGL with NK activity.     

Leukemic CD3+ LGL share functional properties with their CD8+ CD57+ cell counterpart expanded after BMT.

Leukemic T-LGL (large granular lymphocyte) composed of clonal CD3+ TCR alphabeta+ CD8+ CD57+ cells were compared with oligoclonally CD3+ CD8hi+ CD57- lymphocytes expanded after BMT. Leukemic CD3+ CD8hi+ CD57+ LGL showed several phenotypic differences such as an upregulation of CD16 and adhesion molecules (mainly CD11c, CD58 and CD54), activation markers and an exclusive CD45RA isoform expression. Unstimulated CD3+ CD8+ CD57+ LGL from both leukemic and BMT donors spontaneously developed an ex vivo CTL-like CD3-redirected cytotoxicity but no NK cell activity. Different stimuli (PHA, PMA or rhIL-2) induced similar cytotoxic profiles after a 6-day culture involving a CD3-redirected lysis predominating over a low NK cell activity. However, culture of leukemic LGL with these stimuli allowed either a 2 week persistence (PMA or rhIL-2) of CD8+ CD57+ LGL or their disappearance after 3 days (PHA). Furthermore, leukemic CD8hi+ CD57+ T lymphocytes produced an inhibitor of cytotoxic functions as previously described for BMT recipients' CD8+ CD57+ cells. Thus, despite some phenotypic differences between both cell sources, leukemic CD57+ T-LGL display the same functional characteristics of cytotoxic effector and immunoregulatory T cells as CD8+ CD57+ T cells from BMT recipients which might represent their normal counterpart.     

Isolated anemia in patients with large granular lymphocytic leukemia (LGLL)

Patients with large granular lymphocytic leukemia (LGLL) frequently present with neutropenia. When present, anemia is usually accompanied by neutropenia and/or thrombocytopenia and isolated anemia is uncommon. We evaluated a cohort of 244 LGLL patients spanning 15 years and herein report the clinicopathologic features of 34 (14%) with isolated anemia. The patients with isolated anemia showed a significantly male predominance (p = 0.001), a lower level of hemoglobulin (p < 0.0001) and higher MCV (p = 0.017) and were less likely to have rheumatoid arthritis (p = 0.023) compared to the remaining 210 patients. Of the 34 LGLL patients with isolated anemia, 13 (38%) presented with pure red cell aplasia (PRCA), markedly decreased reticulocyte count and erythroid precursors, and more transfusion-dependence when compared to non-PRCA patients. There was no other significant clinicopathologic difference between PRCA and non-PRCA patients. 32 patients were followed for a median duration of 51 months (6–199). 24 patients were treated (11/11 PRCA and 13/21 non-PRCA patients, p < 0.02). The overall response rate to first-line therapy was 83% [8/11 (72.7%) for PRCA, 12/13 (92.3%) for non-PRCA], including 14 showing complete response and 6 showing partial response with a median response duration of 48 months (12–129). Half of non-PRCA patients who were observed experienced progressive anemia. During follow-up, no patients developed neutropenia; however, 5/27 (18.5%) patients developed thrombocytopenia. No significant difference in overall survival was noted between PRCA and non-PRCA patients. In summary, this study demonstrates the unique features of LGLL with isolated anemia and underscores the importance of recognizing LGLL as a potential cause of isolated anemia, which may benefit from disease-specific treatment. LGLL patients with PRCA were more likely to require treatment but demonstrated similar clinicopathologic features, therapeutic responses, and overall survival compared to isolated anemia without PRCA, suggesting PRCA and non-PRCA of T-LGLL belong to a common disease spectrum.Subject terms: Leukaemia, Leukaemia     

A case of clinical indolent natural killer cell lineage large granular lymphocytic leukemia in a patient with rheumatoid arthritis

We report a case of natural killer (NK) cell leukemia with unusual biological features in a 65-year-old woman with a 20-year history of rheumatoid arthritis. She presented with neutropenia, thrombocytopenia, splenomegaly and bone marrow infiltration. Immunophenotyping (CD2+ CD3- CD4- CD5- CD8- CD16+ CD56-) confirmed NK cell leukemia. Her neutropenia and thrombocytopenia resolved following splenectomy and she has remained well with stable disease for 12 months on oral low-dose methotrexate. In contrast to all previous reports, in this instance the phenotype of large granular lymphocytic (LGL) leukemia occurring in the context of rheumatoid arthritis was NK-cell rather than T-cell. Furthermore, the clinical course was indolent, whereas, all prior literature reports have described a very aggressive clinical course for this disorder with a median survival of just 3.5 months. This case illustrates previously unrecognized heterogeneity in the natural history of this disorder.     

A novel natural killer cell line (KHYG-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation.

We present the establishment of a natural killer (NK) leukemia cell line, designated KHYG-1, from the blood of a patient with aggressive NK leukemia, which both possessed the same p53 point mutation. The immunophenotype of the primary leukemia cells was CD2+, surface CD3-, cytoplasmic CD3epsilon+, CD7+, CD8alphaalpha+, CD16+, CD56+, CD57+ and HLA-DR+. A new cell line (KHYG-1) was established by culturing peripheral leukemia cells with 100 units of recombinant interleukin (IL)-2. The KHYG-1 cells showed LGL morphology with a large nucleus, coarse chromatin, conspicuous nucleoli, and abundant basophilic cytoplasm with many azurophilic granules. The immunophenotype of KHYG-1 cells was CD1-, CD2+, surface CD3-, cytoplasmic CD3epsilon+, CD7+, CD8alphaalpha+, CD16-, CD25-, CD33+, CD34-, CD56+, CD57-, CD122+, CD132+, and TdT-. Southern blot analysis of these cells revealed a normal germline configuration for the beta, delta, and gamma chains of the T cell receptor and the immunoglobulin heavy-chain genes. Moreover, the KHYG-1 cells displayed NK cell activity and IL-2-dependent proliferation in vitro, suggesting that they are of NK cell origin. Epstein-Barr virus (EBV) DNA was not detected in KHYG-1 cells by Southern blot analysis with a terminal repeat probe from an EBV genome. A point mutation in exon 7 of the p53 gene was detected in the KHYG-1 cells by PCR/SSCP analysis, and direct sequencing revealed the conversion of C to T at nucleotide 877 in codon 248. The primary leukemia cells also carried the same point mutation. Although the precise role of the p53 point mutation in leukemogenesis remains to be clarified, the establishment of an NK leukemia cell line with a p53 point mutation could be valuable in the study of leukemogenesis.     

Demonstration of clonality, by X-linked DNA analysis, in chronic natural killer cell lymphocytosis and successful therapy with oral cyclophosphamide.

The expanded lymphocyte population in large granular lymphocyte (LGL)-leukemia carries the phenotypic characteristics of either cytotoxic T lymphocytes (CD3+,CD8+) or natural killer (NK) cells (CD3-,CD15+). In the former subset, clonality has been demonstrated by T-cell receptor gene rearrangement studies. Since NK cells do not rearrange T-cell receptor genes, the neoplastic nature of chronic NK cell lymphocytosis has not been well defined. We used X-linked DNA analysis to study the clonal nature of an expanded NK cell population in a patient with a 3-year history of relative lymphocytosis associated with anemia and neutropenia. Southern blot analysis showed no clonal T-cell receptor gene rearrangement. The majority of the circulating lymphocytes had a NK cell phenotype and demonstrated both direct NK cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity. However, the in vitro growth characteristics of these cells did not suggest that they were polyclonal expansions of normal NK cells. To determine directly the clonal origin of these cells, we performed X-linked DNA analysis. Density gradient centrifugation methods were used to isolate mononuclear cells, and NK cells were positively selected by CD16-immunoconjugated magnetic beads. The DNA of these cells was analyzed by restriction fragment length polymorphism-methylation strategy and showed a monoclonal pattern of X-chromosome inactivation while a polyclonal pattern was obtained in corresponding skin tissue. Treatment of the patient with oral cyclophosphamide resulted in complete hematologic remission. We conclude that chronic NK lymphocytosis may be clonal and responsive to immunosuppressive therapy.     

Establishment of the T-cell large granular lymphocyte leukemia cell line MOTN-1 carrying natural killer-cell antigens

A novel interleukin-2 (IL-2) dependent leukemia cell line MOTN-1 was established from the peripheral blood of a 63-year-old woman with T-cell large granular lymphocyte (LGL) leukemia in chronic phase. Primary peripheral blood leukemia cells were CD3+, CD5+, CD7+, CD56+, CD94+, CD161+, TcRalphabeta+, and HLA-DR+. The immunoprofile of the established cell line MOTN-1, however, showed CD3-, CD5-, CD7+, CD56+, CD94+, CD159+, CD161+, TcRalphabeta- and HLA-DR+; the MOTN-1 cells were cytoplasmatically positive for CD3varepsilon and the products of the T-cell receptor (TcR) genes beta and gamma. While the TcRbeta and TcRgamma genes were rearranged, the TcRdelta gene was found to be deleted. DNA fingerprinting and chromosome analysis identifying the t(2;6)(q?23;q?21) and t(12;18)(q13;q?22) alterations demonstrated the authenticity and the malignant nature of the cell line. The scientific significance of MOTN-1 lies in (1) the rarity of this type of leukemia cell lines, (2) the co-expression of various T- and natural killer (NK)-cell-associated markers, and (3) its unique chromosomal aberrations.     

CD52 expression in T-cell large granular lymphocyte leukemia--implications for treatment with alemtuzumab

Few reports on the successful treatment of T-cell large granular lymphocyte (LGL) leukemia with the humanized anti-CD52 monoclonal antibody alemtuzumab are emerging in the literature. The expression of CD52 by LGLs has not been previously investigated. Using semi-quantitative 2- and 3-color flow cytometry, we documented the expression of CD52 in 100% of abnormal cells in T-cell LGL leukemia (n = 11) and natural killer (NK) cell LGL leukemia (n = 2), and showed no significant difference in CD52 expression between T-cell prolymphocytic leukemia (PLL) and T-cell LGL leukemia. Higher CD52 expression has been noted in responders to alemtuzumab in T-cell PLL and in chronic lymphocytic leukemia (CLL), a B-cell disorder. The strong and consistent expression of CD52 shown here highlights the potential role of alemtuzumab in the treatment of refractory T-cell LGL leukemia and possibly aggressive NK cell leukemia.     

Acute myeloid leukemia cell lines MOLM-17 and MOLM-18 derived from patient with advanced myelodysplastic syndromes

The two acute myelomonocytic leukemia sister cell lines MOLM-17 and MOLM-18 and the Epstein-Barr-virus positive non-malignant B-lymphoblastoid cell lines (B-LCLs) B422 and B423 were established from the bone marrow sample of a 60-year-old Japanese male in the advanced leukemic phase of refractory anemia with excess of blasts, a subtype of myelodysplastic syndromes (MDS). MOLM-17/-18 are proliferatively responsive to the growth factors present in the culture supernatant of the 5637 cell line. The B-LCLs are constitutively growth factor-independent. MOLM-17 and B422 were established at eight months after the initial diagnosis, while MOLM-18 and B423 were derived from a sample one month later. Immunophenotyping of the first leukemia sample revealed a mixed lineage leukemia immunophenotype with positivity for terminal deoxynucleotidyl transferase (TdT), CD13 and CD19; the second sample revealed solely myeloid characteristics with positivity for CD13, CD41 and CD61, whereas TdT was negative. MOLM-17/-18 showed immunomarker profiles typical of the myelomonocytic lineage. The karyotype analysis of MOLM-17/-18 revealed various non-random numerical and structural abnormalities including del(5)(q?), -7, der(11)add(11)(p11.2)add(11)(q23), add(17)(p11.2), add(18)(p11.2), -20, -22 as common aberrations. Treatment with tumor necrosis factor-alpha induced pronounced cellular differentiation of both cell lines into macrophage-like cells. The overall profile of MOLM-17/-18 based on their extensive immunological, cytogenetic and functional characterization suggests that these cell lines together with the paired B-LCLs B422 and B423 may represent scientifically significant in vitro models which could facilitate investigations into the pathobiology of MDS.     

Clinical spectrum of gammadelta+ T cell LGL leukemia: analysis of 20 cases

We report on the clinico-biological characteristics of 20 cases of gammadelta T cell large granular lymphocyte (LGL) leukemia. All the data were compared to that of 196 cases with alphabeta T cell subtype, which represents the majority of T cell LGL leukemias. Clinical findings were quite similar in the two groups regarding age, sex ratio, recurrent infections, and association with auto-immune diseases especially rheumatoid arthritis. Gammadelta LGL predominantly expressed a CD3+/CD4-/CD8+/CD16+/CD57+ phenotype, in 50% of cases. Clinical outcome was favorable for these patients with overall survival of 85% at 3 years. Fifty percent of gammadelta patients required treatment and the response to therapy was estimated at 55%. gammadelta and alphabeta T cell LGL leukemia harbor a very similar clinico-biological behavior and represent part of an antigen-driven T cell lymphoproliferation.     

Epstein-Barr virus associated diffuse large B-cell lymphoma complicated by autoimmune hemolytic anemia and pure red cell aplasia.

A 53-year old man with systemic lymphadenopathy and hepatosplenomegaly was diagnosed with diffuse large B cell-lymphoma after inguinal lymph node biopsy. Anemia was noted, direct and indirect Coombs tests were positive, and the haptoglobin level was low. However, the bone marrow aspirate revealed erythroid aplasia. Co-existing autoimmune haemolytic anemia (AIHA) and pure red cell aplasia (PRCA) were diagnosed. In situ hybridization with Epstein-Barr virus (EBV) encoded small RNA (EBER) showed positive findings in lymphoma cells. Southern blot hybridization revealed immunoglobulin heavy chain gene rearrangement and a clonal EBV terminal repeat, indicating monoclonal proliferation of EBV in infected B cells. The patient was treated with CHOP, resulting in a complete remission (CR). AIHA and PRCA subsided after 3 courses of chemotherapy. In conclusion, this case demonstrates not only the association of B-cell lymphoma with autoimmune disorders but also the involvement of EBV in these conditions.     

Acute transformation of chronic large granular lymphocyte leukemia associated with additional chromosome abnormality

A patient with large granular lymphocyte (LGL) leukemia that transformed into an acute or aggressive form after 20 months of the chronic phase is reported. The patient's leukemic cells were mature, medium-sized lymphocytes with sparse azurophil granules and the surface phenotypes of the cells were CD2+, CD3-, CD11+, and CD16+. Molecular analysis showed a germ line configuration in both T-cell receptor beta-chain genes and T-cell receptor tau-chain genes. A clonal anomaly of chromosome (trisomy 8) was demonstrated in peripheral blood cells. LGL after acute transformation of the disease displayed large blastic morphology with prominent nucleoli, intense basophilic cytoplasm, and numerous granules. Karyotypic analysis demonstrated a mosaic of trisomy 8 and trisomy 8 with an additional marker chromosome. Thus, transformation of chronic LGL leukemia into an acute or aggressive form in this patient was associated with morphologic and karyotypic changes of the leukemic cells. Patients with a stable form of chronic LGL leukemia should be examined carefully for the possible acute crisis associated with a clonal evolution.     

X连锁高IgM综合征合并T细胞大颗粒淋巴细胞白血病一例并文献复习

目的探讨X连锁高IgM综合征(XHIGM)的临床特征、诊断要点、治疗方法等。方法回顾性分析中国医学科学院血液病医院2020年3月收治的1例23岁XHIGM合并T细胞大颗粒淋巴细胞白血病(T-LGLL)患者的临床特征及实验室资料,并进行文献复习。结果患者,男性,17岁开始出现反复感染症状,就诊后发现中性粒细胞减少、贫血伴有明显脾大,IgG、IgA水平减低。虽然IgM低于正常水平(典型XHIGM表现为IgM正常或升高),但通过二代测序证实该患者为CD40L基因纯合突变(染色体:chrX;位置:135730438;氨基酸变异情况:NM_000074:exon1:c.31C>T:p.R11X;突变类型:无义突变);其母亲检测到该基因突变位点为杂合突变,其父亲未检测到该基因突变。患者明确诊断为XHIGM。患者脾切除术后贫血和中性粒细胞减少得以缓解,因白细胞升高,依据流式细胞术检测、TCR基因重排呈阳性和骨髓病理免疫组织化学染色结果表明T细胞大颗粒淋巴细胞增高且为克隆性增殖。患者最终诊断为XHIGM合并T-LGLL。结论少数XHIGM患者可在成年后发病,且可表现为IgG、IgA和IgM水平均明显减低的非典型临床特征,CD40L基因突变是XHIGM最终的确诊标准。对于反复感染、IgG定量低于正常水平、合并中性粒细胞减少的男性患者,需进行XHIGM基因筛查。少数XHIGM患者可合并T-LGLL。     

Fulminant clonal expansion of large granular lymphocytes. Characterization of their morphology, phenotype, genotype, and function

A 39-year-old woman exhibited abrupt malignant transformation of the large granular lymphocytes (LGL) after a chronic course of T gamma-lymphoproliferative disease (T gamma-LPD). The T gamma-lymphocytes were CD2+, CD3-, CD8-, CD16+, Leu7-, and Leu19+ with morphologic characteristics of LGL. Newly appearing LGL were much larger and had more prominent azurophilic granules. Although fundamentally they had the same phenotype as the LGL in chronic stage, they showed increased Ia-like antigen and decreased CD16 antigen expressions. Immunoglobulin (Ig) G-kappa type monoclonal component was detected in the patient's serum. The LGL showed a germ-line configuration for T-cell receptor (TCR) beta and gamma chain genes, whereas the clonal chromosomal abnormalities indicated the neoplastic nature of the LGL. The LGL exhibited competent natural killer (NK), interleukin 2 (IL2) activated killer (AK), and antibody-dependent cell-mediated cytotoxicity (ADCC) activities. The LGL may have derived from NK cells at their mature stage with prethymic phenotype and may have influenced the homeostasis of the patient's humoral immune response.     

Granular lymphocytic leukemia derived from gamma delta T-cell expressing cytotoxic molecules

We here present an extremely rare case of granular lymphocytic leukemia derived from gamma delta T-cell (gamma delta T-GLL). The blood picture at diagnosis was as follows; white cell count 25.7 x 10(9)/l containing 94% atypical lymphocytes with cytoplasmic granules, hemoglobin 11.8 g/dl and platelet count 124 x 10(9)/l. The atypical lymphocytes were positive for CD2, CD3, CD5, CD7, CD56 and TCR gamma delta, but negative for CD4, CD8, CD57, TCR alpha beta and B-cell antigens. The cytotoxic molecules, T-cell intracellular antigen-1 (TIA-1) and granzyme B, were positive by immunocytochemical analysis. Southern blot analysis showed rearrangement of T-cell receptor J gamma and C beta genes but germline configuration of the JH gene. Neither serum antibody against human T-cell leukemia virus type-I (HTLV-I) nor the integration of HTLV-I proviral DNA was detected. CT scan showed splenomegaly but no lymph node enlargement. A diagnosis of gamma delta T-GLL was made, and she has been followed up without any therapies for more than 4 years.