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

Ohno, Y; Amakawa, Ryuichi; Fukuhara, Shirou; Huang, Cheng‐Rong; Kamesaki, H; Amano, Hiroyuki; Imanaka, Toshinobu; Takahashi, Yutaka; Arita, Yu; Uchiyama, Takashi; Kita, K; Miwa, Hiroshi

doi:10.1002/1097-0142(19890701)64:1<63::aid-cncr2820640111>3.0.co;2-#

Cited by 51 publications

(30 citation statements)

References 14 publications

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“…As previously described for CD8 ϩ and CD4 ϩ T-cell LGL-leukemia, transformation of CNKCL into aggressive NK cell malignancies may occur suggesting that both T-cell and NK cell LGL-leukemia could be premalignant conditions. [61][62][63][64][65] In such cases, new chromosomal abnormalities are frequently detected suggesting that the malignant clinical behavior of the disease could probably depend on additional oncogenic events. 61,62 In line with these findings, one of our patients with longer follow-up had evidence for disease progression with lung infiltration.…”

Section: Discussionmentioning

confidence: 99%

Clinicobiological, Immunophenotypic, and Molecular Characteristics of Monoclonal CD56−/+dim Chronic Natural Killer Cell Large Granular Lymphocytosis

Lima

Almeida

Montero

et al. 2004

The American Journal of Pathology

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Indolent natural killer (NK) cell lymphoproliferative disorders include a heterogeneous group of patients in whom persistent expansions of mature, typically CD56 ؉ , NK cells in the absence of any clonal marker are present in the peripheral blood. In the present study we report on the clinical, hematological, immunophenotypic, serological, and molecular features of a series of 26 patients with chronic large granular NK cell lymphocytosis, whose NK cells were either CD56 ؊ or expressed very low levels of CD56 (CD56 ؊/؉dim NK cells), in the context of an aberrant activation-related mature phenotype and proved to be monoclonal using the human androgen receptor gene polymerase chain reaction-based assay. As normal CD56 ؉ NK cells, CD56 ؊/؉dim NK cells were granzyme B ؉ , CD3 ؊ , TCR␣␤/ ␥␦ ؊ , CD5 ؊ , CD28 ؊ , CD11a ؉bright , CD45RA ؉bright , CD122 ؉ , and CD25 ؊ and they showed variable and heterogeneous expression of both CD8 and CD57. Nevertheless, they displayed several unusual immunophenotypic features. Accordingly, besides being CD56 ؊/؉dim , they were CD11b ؊/؉dim (heterogeneous), CD7 ؊/؉dim (heterogeneous), CD2 ؉ (homogeneous), CD11c ؉bright (homogeneous), and CD38 ؊/؉dim (heterogeneous). Moreover, CD56 ؊/؉dim NK cells heterogeneously expressed HLA-DR. In that concerning the expression of killer receptors, CD56 ؊/؉dim NK cells showed bright and homogeneous CD94 expression, and dim and heterogeneous reactivity for CD161, whereas CD158a and NKB1 expression was variable. From the functional point of view, CD56 ؊/؉dim showed a typical Th1 pattern of cytokine production (interferon-␥ ؉ , tumor necrosis factor-␣ ؉ ). From the clinical point of view, these patients usually had an indolent clinical course, progression into a massive lymphocytosis with lung infiltration leading to death being observed in only one case. Despite this, they frequently had associated cytopenias as well as neoplastic diseases and/or viral infections. In summary, we describe a unique and homogeneous group of monoclonal chronic large granular NK cell lymphocytosis with an aberrant activation-related CD56 ؊/؉dim /CD11b ؊/؉dim phenotype and an indolent clinical course, whose main clinical features are related to concomitant diseases. (Am J

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Section: Discussionmentioning

confidence: 99%

Clinicobiological, Immunophenotypic, and Molecular Characteristics of Monoclonal CD56−/+dim Chronic Natural Killer Cell Large Granular Lymphocytosis

Lima

Almeida

Montero

et al. 2004

The American Journal of Pathology

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“…Clinical samples from patients with leukemia were cryopreserved in our laboratory as described previously. [46][47][48] Normal peripheral mononuclear cells (PBMCs) were purified from healthy donor with informed consent; normal CD4 ϩ T cells and normal CD56 ϩ cells were purified using magnetic-activated cell sorting (MACS) CD4 ϩ T-cell isolation kit (Miltenyi Biotec, Bergisch Gladbach, Germany) and MACS CD56 ϩ isolation kit (Miltenyi Biotec), respectively. All the clinical samples were taken with informed consent and used only for in vitro study following the guideline of the institutional review board of Kyoto University.…”

Section: Cells and Cell Culturementioning

confidence: 99%

Kpm/Lats2 is linked to chemosensitivity of leukemic cells through the stabilization of p73

Kawahara

Hori

Chonabayashi

et al. 2008

Blood

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Down-regulation of the Kpm/Lats2 tumor suppressor is observed in various malignancies and associated with poor prognosis in acute lymphoblastic leukemia. We documented that Kpm/Lats2 was markedly decreased in several leukemias that were highly resistant to conventional chemotherapy. Silencing of Kpm/Lats2 expression in leukemic cells did not change the rate of cell growth but rendered the cells more resistant to DNA damageinducing agents. Expression of p21 and IntroductionThe Warts (Wts) tumor suppressor gene (also termed Lats after large tumor suppressor) was first identified by mitotic recombination of somatic cells and screening for homozygous mutants with overproliferation phenotype in Drosophila melanogaster. 1,2 This discovery initiated a series of genetic studies in Drosophila that led to the delineation of a new signaling network named the Hippo pathway, which is now known to regulate cell growth, cell survival, and organ size in developing animals. [3][4][5] This pathway consists of a kinase cascade in its core where Hippo (Hpo) phosphorylates and activates Wts/Lats, 6 which then in turn phosphorylates and inactivates Yorkie (Yki), a transcription coactivator. Inactivation of Yki results in control of cell survival and cell growth through downregulation of Drosophila inhibitor of apoptosis 1 (Diap1) and Cyclin E. 7 Salvador (Sav), 8,9 a scaffold protein for Hpo, and Mats (mob as tumor suppressor), 10-12 a partner and potentiater of Wts, are also essential components of this pathway. Furthermore, recent evidence has placed Expanded (EX), Merlin (Mer), 13 both 4.1 family proteins, and Fat (FT), 14-17 the atypical cadherin, in the upstream of the Hippo pathway although their connection to the kinase cascade is largely based on genetic epitasis. The Hippo pathway is believed to be conserved throughout species because some of the mammalian homologues have been shown to compensate the corresponding defects in the Drosophila Hippo pathway. At present, however, only a small part of the mammalian Hippo pathway has been experimentally substantiated.Kpm (alternatively named Lats2) is one of the 2 human homologues of Drosophila Wts. 18,19 In parallel to Drosophila Wts, we and others have shown the critical involvement of Kpm/Lats2 in regulation of cell growth and survival. Kpm/Lats2 overexpression results in the cell cycle arrest in G2/M phase via inhibition of Cdc2-Cyclin B kinase activity leading eventually to apoptosis, 20 inhibition of G1/S transition via down-regulation of Cyclin E/Cdk2 kinase activity, 21 or apoptosis via down-regulation of Bcl-2 and Bcl-xL. 22 Kpm/Lats2 binds to Mdm2 and inhibits its E3 ubiquitin ligase activity, resulting in the stabilization of p53 and leading to the p53-dependent G1/S arrest in nocodazole-treated cells. 23 Moreover, Kpm/Lats2 is a target gene of p53 both in mammalian as well as in Drosophila cells, 24,25 suggesting that Kpm/Lats2 may be a positive-feedback-loop regulator of p53. Kpm/Lats2 knockout mice are embryonically lethal and fibroblasts isolated from these mice app...

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“…Clinically, the disease presents with an indolent course, and no cytogenetic abnormalities are usually found. Although the disease itself has uncertain malignant potential, rare cases may develop into ANKL [230][231][232] . However, this may represent the presence of occult ANKL miscategorized as CNKL rather than transformation.…”

Section: Chronic Nk-lymphocytosismentioning

confidence: 99%

Leukemia and Lymphoma of Natural Killer Cells

Suzuki

2005

J Clin Exp Hematopathol

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Malignant hematolymphoid disorders arising from NK cells have become widely recognized over the past decade. The two forms of NK-cell malignancy, aggressive NK-cell leukemia (ANKL) and extranodal NK-cell lymphoma of nasal type (ENKL) are both characterized by the proliferation of tumor cells with an NK-cell like immunophenotype. ANKL usually presents with bone marrow tumor cells accompanied by circulating leukemic cells, and hepatosplenomegalay is a common clinical feature. ENKL most frequently affects the nasal or paranasal regions, with cutaneous involvement also being common. Approximately 70 percent of ENKL present with localized tumor cells, and follow an indolent clinical course, but, in advanced cases, tumors rapidly expand and are frequently fatal. Tumor cells from both ANKL and ENKL are surface CD3 − and CD56 + but differ in their expression of CD16. Epstein-Barr virus (EBV) is found in most cases of NK-cell leukemia/lymphoma, suggesting an oncogenic role, but patients may have biclonal or polyclonal populations of malignant cells based on differential EBV genome incorporation. NK-cell neoplasms are frequently resistant to chemotherapy due to p-glycoprotein expression and associated multidrug resistance. The prognoses of both localized and advanced stages of NK-cell malignancies are worse than most other lymphoid malignancies, but studies are currently underway to assess the safety and efficacy of novel chemoradiotherapy regimens for the treatment of these neoplasms.

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

Cited by 51 publications

References 14 publications

Clinicobiological, Immunophenotypic, and Molecular Characteristics of Monoclonal CD56−/+dim Chronic Natural Killer Cell Large Granular Lymphocytosis

Clinicobiological, Immunophenotypic, and Molecular Characteristics of Monoclonal CD56−/+dim Chronic Natural Killer Cell Large Granular Lymphocytosis

Kpm/Lats2 is linked to chemosensitivity of leukemic cells through the stabilization of p73

Leukemia and Lymphoma of Natural Killer Cells

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