Cell Precursor Acute Leukemia Research Articles

Molecular profiling of myeloid/natural killer (NK) cell precursor acute leukemia

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described based on its clinical phenotype and immunophenotype, and proposed as a unique leukemia entity. However, due to its rarity and lack of defined distinctive molecular characteristics, there is currently no international consensus on this disease concept. We performed multi-omics analysis and revealed that MNKPL is distinct from acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia. NOTCH1 and RUNX3 activation and BCL11B downregulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, our single-cell analysis using MNKPL cells suggested that NK cells and myeloid cells share common progenitor cells. Our retrospective case study uncovered that outcomes of MNKPL are unsatisfactory, even with hematopoietic cell transplantation. Multi-omics analysis and in vitro drug sensitivity assays revealed increased sensitivity to L-asparaginase and reduced levels of asparagine synthetase, supporting the clinically observed effectiveness of L-asparaginase.

Myeloid/natural killer (NK) cell precursor acute leukemia as a distinct leukemia type

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and NOTCH1 and RUNX3 activation and BCL11B down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage–derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l -asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l -asparaginase.

Mapping the genetic features of T-ALL cases through simplified NGS approach

BackgroundDespite the irruption of massive sequencing technologies in clinical routine, the genetic diagnosis of T-cell acute lymphoblastic leukemia (T-ALL) continues to be based on traditional techniques. The integration of old and new technologies with diagnostic and prognostic purposes represents a major challenge. MethodsA High-Throughput Sequencing (HTS) approach was applied to analyze the genetic landscape of two patients diagnosed with T-ALL and one early T cell precursor acute leukemia. Orthogonal standard techniques were used to confirm the findings of NGS analysis. ResultsBy using a single test, a complete genetic map including 2 previously unreported missense mutations in BCL11B gene are reported. Cooperating oncogenic lesions including CDKN2A/B deletions, SIL-TAL1 rearrangement and FLT3 amplification were also captured by using a single test. ConclusionsHTS is a useful approach that allows simultaneously analyzing mutations, CNVs and the clonal repertoire in T-ALL patients. This approach may simplify the genetic assessment of ALL.

Comprehensive Genetic Analysis Revealed Myeloid/Natural Killer (NK) Cell Precursor Acute Leukemia As a Novel Distinctive Leukemia Entity

Introduction: Myeloid/Natural killer (NK) cell precursor acute leukemia (MNKPL) is a rare hematologic malignancy prevalent in East Asia. MNKPL is characterized by extramedullary involvement, immature lymphoblastoid morphology without myeloperoxidase (MPO) reactivity, the CD7+/CD33+/CD34+/CD56+/HLA−DR+ phenotype. MNKPL is classified as mixed phenotype acute leukemia, and not otherwise specified rare types (MPAL NOS rare types) in WHO classification. However, its characteristic clinical feature and undetermined genetic feature suggests that MNPKL leaves open the possibility of a new independent disease concept. Here, we report clinical features and genetic alterations in patients with MNKPL. Methods: The Leukemia and Lymphoma Committee of the Japanese Society of Pediatric Hematology and Oncology (JSPHO) sent out questionnaires to 110 JSPHO affiliated hospitals and collected cases of MNPKL diagnosed during the period 2000-2013. Besides, the cases published as literature were recruited. The data of clinical features, cell surface antigen profiling, overall survival (OS), and event-free survival (EFS) defined as relapse or death were also collected as a secondary survey. The protocol of this retrospective study was approved by the review boards of JSPHO and Ehime Prefectural Central Hospital. Comprehensive genetic analysis including 13 whole-exome sequences (WES), 2 target sequence, 6 RNA sequence (RNA-seq), and 8 DNA methylation analysis was performed. We also performed single-cell RNA-seq using 1 sample of MNKPL patients and a normal bone marrow sample as the reference. The research protocol was approved by the review board of TMDU. Results: Sixteen children or young adults (< 39 years old) and 2 older adults with MNKPL were identified. The median age of MNKPL patients was 11 (0.5-75) years old. There are 12 males and 6 females. The extramedullary involvement was observed in 7 patients. Complete remission after induction therapy was achieved in 8/14 (57%) patients treated with acute myeloid leukemia (AML) type chemotherapy and 2/4 (50%) patients treated with acute lymphoblastic leukemia (ALL)/non-Hodgkin lymphoma type chemotherapy, respectively. Fifteen patients underwent hematopoietic cell transplantation (HCT). The median follow-up period was 3.8 (0.1-16.0) years. 5-year OS and 5-year EFS was 49.5% and 40.7%, respectively. In genetic analysis, median 388 somatic mutations in MNKPL were identified by WES. The recurrent mutations were observed in NOTCH1 (n=5), MAML3 (n=4), NRAS, MAP3K4, RECQL4, CREBBP, ASXL2, and KMT2D (n=3, respectively), and MAML2, MAP3K1, FLT3, CARD11, MSH4, FANCI, WT1, ZNF384, and ERG (n=2, respectively). The distinct expression pattern, higher expression of RUNX3 and NOTCH1, and lower expression of BCL11B were identified in MNKPL samples which were compared to MPAL, AML, and T cell ALL in RNA-seq. The distinct methylation profile, hypomethylation of RUNX3 regulatory region, and hypermethylation of BCL11B regulatory region were identified in DNA methylation analysis. Single-cell RNA-seq analysis also showed distinct 4 subsets of MNKPL. Discussion and Conclusions: NK cells are the founding member of a family of innate lymphoid cells (ILC). Genetic abnormality of NOTCH1 pathway is a hallmark of MNPKL. RUNX3 is required for NK cell survival and proliferation in response to IL-15 signaling. RUNX3 high expression and hypomethylation of RUNX3 regulatory region also characterize MNKPL. Currently, MNKPL is classified as MPAL NOS, our genetic analysis revealed that MNKPL is a distinct group from MPAL. The prognosis of MNKPL was not satisfactory even though HCT was performed. The development of new therapeutic approaches based on these genetic analyses is highly expected. Disclosures Saito: Toshiba Corporation: Research Funding. Nakazawa:Toshiba Corporation: Research Funding.

Clinical Feature and Genetic Alterations in Myeloid/Natural Killer (NK) Cell Precursor Acute Leukemia and Myeloid/NK Cell Acute Leukemia

Introduction: Myeloid/Natural killer cell precursor acute leukemia (MNKPL) and myeloid/NK cell acute leukemia (MNKL) is a rare hematologic malignancy prevalent in East Asia. MNKPL is characterized by marked extramedullary involvement, immature lymphoblastoid morphology without myeloperoxidase (MPO) reactivity, a CD7+/CD33+/CD34+/CD16−/CD15−/+/HLA-DR+ phenotype, myeloid chemosensitivity, and a poor prognosis. By contrast, MNKL shows no extramedullary involvement, a HLA‐DR−/CD33+/CD16−/CD34−/+ phenotype, myeloid chemosensitivity, and a good prognosis. However, analysis of outcome and genetic alterations in these leukemias are limited. Here, we report outcome and genetic alterations in the patients with MNKPL and MNKL.Methods: The Leukemia and Lymphoma Committee of the Japanese Society of Pediatric Hematology and Oncology (JSPHO) sent out two questionnaires to 110 JSPHO affiliated hospitals. The first questionnaire requested details of the number of pediatric patients with MNKPL or MNKL had been diagnosed during the period 2000-2013. The second questionnaire requested more detailed information about clinical curses. Overall survival (OS) and event free survival (EFS) defined as relapse or death was analyzed. The protocol of this retrospective study was approved by the review boards of JSPHO and Ehime Prefectural Central Hospital.We also performed whole exome sequence (WES) using 7 children's samples (5 MNKPL, 2 MNKL) and target sequence using 2 adult's samples (2 MNKPL) from this and another independent cohort. The research protocol was approved by the review board of TMDU.Results: Thirteen children with MNKPL and 6 children with MNKL were identified. Median age of MNKPL was 8 year-old (range; 0.5-17) and median age of MNKL was 10 year-old (range; 2-13). There are 8 males and 5 females in MNKPL and 4 males and 2 females in MNKL. In MNKPL, central nervous system, mediastinum and lymph node involvement was observed in 1 case respectively. Nasal sinus involvement was observed in 1 case in MNKL. Eleven patients with MNKPL and 3 patients with MNKL were treated with acute myeloid leukemia style chemotherapy and 1 MNKPL patients and 3 MNKL patients were treated with acute lymphoblastic leukemia/non-Hodgkin lymphoma style chemotherapy. Complete remission after induction therapy was achieved in 8/13 MNKPL children and 4/6 MNKL children. Twelve out of 13 MNKPL children and all 6 MNKL children underwent hematopoietic cell transplantation (HCT) with myeloablative conditioning regimen. Median follow up period was 5.3 years in MNKPL and 3.8 years in MNKL patients. 5-year OS of MNKPL and MNKL was 67.3 % and 41.7 %, 5-year EFS of MNKPL and MNKL was 52.7 % and 41.7 % respectively.In genetic analysis, average 148 somatic mutations in MNKPL and 88 somatic mutations in MNKL were identified by WES. In combined analysis using adult cases, the recurrent mutations were observed in NOTCH1, NRAS (n=3, respectively), MAML2, MAP3K1, SIRPA (n=2, respectively) as activating signal genes, and CLTCL1 (n=2) as cell adhesion molecules, and RECQL4 (n=2) as cell cycle/DNA repair molecules, and PRDM2, CREBBP, SETBP1 (n=2, respectively) as epigenetic modifiers, and WT1, ZNF384, BCLAF1 (n=2, respectively) as transcription factors.Conclusions: Previously, it has been reported that outcome of MNKL is relatively good than MNKPL. MNKPL and MNKL children had a poor prognosis in our cohort even though most patients received HCT. We identified alteration of molecules involved in NOTCH signaling and RAS-MAPK pathways. In addition, mutations of several transcription factors such as WT1 were identified. The drugs targeting RAS pathway and epigenetic factors may have the potential to improve outcome. An international collaboration for clinical and cytogenetic research of MNKPL and MNKL is needed as they are complex and rare diseases. DisclosuresNo relevant conflicts of interest to declare.

Current views of pediatric B cell precursor acute leucoyteic leukemia.

The most common type cancer prevailing in pediatric patients worldwide is acute lymphoblastic leukemia (ALL). The characteristic feature of this cancer is the accumulation of immature lymphoid cell in the bone marrow. Further a subtype of ALL namely B-cell precursor (BCP)-ALL has raised in the recent years and is the most common subtype of ALL prevalent in children worldwide. The present review article will put light on the current aspects of BCP ALL including etiology, causative factors, diagnostic and treatment.

Sjögren's Syndrome Complicated by Myeloid/Natural Killer Cell Precursor Acute Leukemia: Case Report and Review of the Literature.

We report a case of Sjögren's syndrome (SS) complicated by myeloid/natural killer (NK) cell precursor acute leukemia (M/NKPAL). A 75-year-old woman with a previous SS history for 2 years was routinely treated. Peripheral blood progenitor cells were increased, and subsequent bone marrow cell morphology examination showed the presence of acute myeloid leukemia type M4. However, flow cytometry analysis revealed that CD7/CD56/CD33/CD34/HLA-DR/cCD3 were all positive and myeloperoxidase- (MPO-) specific staining, other T cells, NK cells, and myeloid markers were all negative. Clonal T-cell receptor (TCR)β/TCRγ/TCRδ gene rearrangements and Epstein-Barr virus (EBV) were negative. The diagnosis of M/NKPAL was therefore confirmed. Unfortunately, this patient did not receive chemotherapy and later died of acute left heart failure and respiratory failure. SS complication with M/NKPAL is relatively rare. Combined with the relevant literatures, our study offers new insights into the clinical characteristics, pathological features, possible pathogenesis, and differential diagnosis of this rare disease.

Aggressive MLL gene rearranged CD7+ CD56+ myeloid/natural killer cell precursor acute leukaemia with extramedullary relapse in the uterus and breast

Aggressive MLL gene rearranged CD7+ CD56+ myeloid/natural killer cell precursor acute leukaemia with extramedullary relapse in the uterus and breast

Beyond Philadelphia: 'Ph-like' B cell precursor acute lymphoblastic leukemias - diagnostic challenges and therapeutic promises.

The presence of the Philadelphia chromosome causing the fusion between BCR to ABL1 in B cell precursor acute lymphoblastic leukemias (ALLs) was associated with a particularly bad prognosis, which has been markedly improved with the addition of imatinib to chemotherapy. Recent genomic studies have lead to the identification of 'Philadelphia like' or 'BCR-ABL1 like' ALLs lacking BCR-ABL1 fusion. About 10% of childhood ALL and a higher percentage of adolescents and adults with ALLs are characterized by activation of cytokine receptors and signaling kinases. Aberrant expression, point mutations or fusion translocations cause activation of either the ABL1 or JAK signaling pathways. In general, these leukemias are associated with worse prognosis. Preclinical studies and limited clinical experience suggest that these leukemias respond to tyrosine kinase inhibitors. Thus, their identification is important. However, as most of these fusion translocations are rare, their diagnosis is challenging. The diagnosis of 'Philadelphia like' poor prognosis ALLs is technically challenging but of paramount importance as they are likely to respond to targeted therapy with currently available ABL or JAK inhibitors.

Myeloid/natural killer cell precursor and myeloid/natural killer cell acute leukemia

With the popularity of flow cytometry, the classification of leukemia become more detailed. Myeloid/natural killer cell precursor acute leukemia and myeloid/natural killer cell acute leukemias are generally recognized as two kinds of rare leukemias and have poor prognosis. The cells expressed both myeloid and lymphatic antigens in these two leukemia and can not be diagnosed by morphology. The only basis to make a definite diagnosis is their unique Immunophenotyping. The role of CD7 and CD56 in these two leukemia are compelling, in the other hand, as the progress of cell differentiation research, there are many new awareness of NK cell differentiation. In this article, the biological origin, clinical manifestation, diagnosis, treatment and the role of CD7 and CD56 in these two leukemia are briefly summarized.

Loss of mismatched HLA in myeloid/NK cell precursor acute leukemia relapse after T cell-replete haploidentical hematopoietic stem cell transplantation

Myeloid/natural killer cell precursor acute leukemia (MNKL) is an aggressive disease with a high relapse rate even after allogeneic hematopoietic stem cell transplantation (SCT). We report a patient with MNKL who had a donor lymphocyte infusion (DLI) for relapse after T cell-replete human leukocyte antigen (HLA)-haploidentical SCT, but relapsed again 20 months later with loss of mismatched HLA. This case suggests that a strong graft-versus-leukemia effect of haploidentical SCT can be expected in MNKL patients. In the haploidentical setting, DLI should be considered for patients with relapsed leukemia whose leukemic cells have not lost HLA cell surface expression.

Myeloid/NK cell acute leukemia with unique blast morphology: de novo or secondary leukemia?

Immature-type natural killer (NK) cell leukemia is rare and heterogeneous, and is variously classified as myeloid/NK cell precursor acute leukemia, myeloid/NK cell acute leukemia, or blastic NK cell lymphoma/leukemia [1–3]. Scott et al. [1] first described 20 cases of adult de novo acute myeloid leukemia showing a CD16/CD33/CD34/ CD56/HLA-DR phenotype. A few additional cases have since been reported, including that presented in this journal [4]. However, Suzuki et al. [2, 3] characterized myeloid/ NK cell precursor acute leukemia as a distinct entity, with a CD7/CD56/CD34/HLA-DR phenotype. Thus, myeloid/NK cell leukemia showing the CD7/CD56/ CD34/HLA-DR phenotype is considered to be more mature than myeloid/NK cell precursor leukemia [3]. Here, we report a case of myeloid/NK cell acute leukemia developing after chemoradiotherapy and with morphologically distinct characteristics. In March 2013, a 63-year-old man presented with poor appetite, lassitude, chest pain, and ophthalmic pain. He had undergone chemoradiotherapy (irradiation with 69.6 Gy/37 Fr and chemotherapy with cumulative doses of 280 mg/body carboplatin and 4,000 mg/body 5FU) for hypopharyngeal squamous cell carcinoma 5 months before referral. His complaints resolved gradually within 1 month; however, he developed anemia (Hb, 7.3 g/dL), thrombocytopenia (platelet count, 36 k/lL), and high lactate dehydrogenase (LDH, 836 IU/ L) in early April 2013. His condition rapidly deteriorated thereafter and he suffered respiratory distress and hepatic/ renal failure. There were no skin lesions, lymphadenopathy, or hepatosplenomegaly. No symptoms suspecting CNS disease were present. Repeat transfusions of red blood cells and platelets were performed. Blood analysis showed the following: white blood cell counts, 3,100/lL (5 % abnormal cells); Hb, 8.7 g/dL; platelet count, 63 K/lL; serum CRP, 2.89 mg/dL; aspartate aminotransferase (AST, 4,169 IU/L); alanine aminotransferase (ALT, 1,191 IU/L); LDH, 6,014 IU/L; total bilirubin, 6.2 mg/dL; direct bilirubin, 4.3 mg/dL; ferritin, 1,036 ng/mL; BUN, 48.2 mg/ dL; creatinine, 3.51 mg/dL; and uric acid, 19.6 mg/dL. The patient then developed coagulopathy, with a plasma D-dimer 2.7 lg/mL (normal \1.0 lg/mL), fibrinogen 140 mg/dL (normal 146–380 mg/dL) and antithrombin-III level of 33 % (normal 80–125 %). The bone marrow smear was cellular and showed 77 % blasts, which possessed round or oval nuclei with prominent nucleoli and a deeply stained cytoplasm with protrusions (mimicking plasmacytoid/megakaryoblastoid cells), some of which (6 %) showed weak staining for myeloperoxidase but stained negative for Periodic Acid-Schiff and iron. There were no azurophilic granules. In addition, we noted very large fishshaped blasts containing numerous nucleoli, large cells with mitotic figures, and unevenly divided binuclear blasts (Fig. 1a–d), Flow cytometry showed that bone marrow blasts were CD33 (80 %)/CD56 (96 %) but CD4 (\5 %)/CD7 (\5 %)/CD13 (\5 %)/CD34 (\5 %)/ CD41 (\5 %)/CD61 (\5 %) and HLA-DR (\5 %). Thus, the diagnosis of myeloid/NK cell leukemia was S. Imashuku (&) N. Kudo Division of Hematology, Takasago-seibu Hospital, 1-10-41 Nakasuji, Takasago 676-0812, Japan e-mail: shinim95@mbox.kyoto-inet.or.jp

Engraftment of low numbers of pediatric acute lymphoid and myeloid leukemias into NOD/SCID/IL2Rcγnull mice reflects individual leukemogenecity and highly correlates with clinical outcome

Although immortalized cell lines have been extensively used to optimize treatment strategies in cancer, the usefulness of such in vitro systems to recapitulate primary disease is limited. Therefore, the design of in vivo models ideally utilizing patient-derived material is of critical importance. In this regard, NOD.Cg-Prkdc(scid) IL2rg(tmWjl) /Sz (NSG) mice have been reported to provide superior engraftment rates. However, limited data exist on the validity of such a model to constitute a surrogate marker for clinical parameters. We studied primary and serial engraftment on more than 200 NSG mice with 54 primary pediatric B cell precursor acute lymphatic leukemia (B-ALL), myeloid leukemia (AML) and T cell leukemia (T-ALL) samples, characterized the leukemogenic profile and correlated engraftment kinetics with clinical outcome. Median time to engraftment was 7-10 weeks and 90% of the mice engrafted. Male recipients conferred significantly higher engraftment levels than female recipients (p ≤ 0.004). PCR-based minimal residual disease marker expression and fluorescence in situ hybridization confirmed the presence of patient-specific genetic aberrations in mice. Transcriptome cluster analysis of genes known to be important in the leukemogenesis of all three diseases revealed that well-known tumor-regulating genes were expressed to a comparable extent in mice and men. The extent of engraftment and overall survival of NSG mice highly correlated with the individual prognosis of B-ALL, AML and T-ALL patients. Thus, we propose an in vivo model that provides a valuable preclinical tool to explore the heterogeneity of leukemic disease and exploit patient-tailored leukemia-targeting strategies within multivariate analyses.

Myeloid/natural killer cell precursor acute leukemia diagnosed by cell marker analysis

Myeloid/natural killer cell precursor acute leukemia diagnosed by cell marker analysis

Fusion Toxin BLyS-Gelonin Inhibits Growth of Malignant Human B Cell Lines In Vitro and In Vivo

B lymphocyte stimulator (BLyS) is a member of the TNF superfamily of cytokines. The biological activity of BLyS is mediated by three cell surface receptors: BR3/BAFF-R, TACI and BCMA. The expression of these receptors is highly restricted to B cells, both normal and malignant. A BLyS-gelonin fusion toxin (BLyS-gel) was generated consisting of the recombinant plant-derived toxin gelonin fused to the N-terminus of BLyS and tested against a large and diverse panel of B-NHL cell lines. Interestingly, B-NHL subtypes mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL) and B cell precursor-acute lymphocytic leukemia (BCP-ALL) were preferentially sensitive to BLyS-gel mediated cytotoxicity, with low picomolar EC50 values. BLyS receptor expression did not guarantee sensitivity to BLyS-gel, even though the construct was internalized by both sensitive and resistant cells. Resistance to BLyS-gel could be overcome by treatment with the endosomotropic drug chloroquine, suggesting BLyS-gel may become trapped within endosomal/lysosomal compartments in resistant cells. BLyS-gel induced cell death was caspase-independent and shown to be at least partially mediated by the “ribotoxic stress response.” This response involves activation of p38 MAPK and JNK/SAPK, and BLyS-gel mediated cytotoxicity was inhibited by the p38/JNK inhibitor SB203580. Finally, BLyS-gel treatment was shown to localize to sites of disease, rapidly reduce tumor burden, and significantly prolong survival in xenograft mouse models of disseminated BCP-ALL, DLBCL, and MCL. Together, these findings suggest BLyS has significant potential as a targeting ligand for the delivery of cytotoxic “payloads” to malignant B cells.

Abstract 3861: Fusion toxin BLyS-gelonin inhibits growth of B-NHL cell lines in vitro and in vivo

Abstract B lymphocyte stimulator (BLyS) is a member of the TNF superfamily of cytokines. BLyS is expressed by cells of myeloid origin and is one of many soluble factors that regulate human B-cell activation. The biological activity of BLyS is mediated by three cell surface receptors: B-cell-activating factor-receptor (BAFF-R/BR3), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA). These receptors are expressed by normal and malignant B-cells at various stages of development. To target malignant B cells expressing BLyS receptors, the recombinant plant-derived toxin gelonin was fused to the N-terminus of BLyS to generate the fusion toxin BLyS-gel. Gelonin is an N-glycosidase that removes a critical adenine from eukaryotic 28S rRNA, disrupting ribosome function and inhibiting protein synthesis. Importantly, gelonin is not toxic to cells unless coupled with a targeting moiety that can enter the cell. BLyS-gel was used to treat a panel of nearly 50 malignant non-Hodgkin lymphoma (NHL) cell lines expressing BLyS receptors. NHL subtypes mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL) and B cell precursor-acute lymphocytic leukemia (BCP-ALL) were preferentially sensitive to BLyS-gel mediated cytotoxicity, with EC50 values in the low picomolar range. BLyS-gel cytotoxicity was mediated primarily by BR3 and TACI in sensitive cell lines; however, cell surface expression of these BLyS receptors did not necessarily confer sensitivity to BLyS-gel. The internalization of BLyS-gel was confirmed in both sensitive and resistant cell lines, indicating resistance was not due to a lack of internalization. As expected, BLyS-gel treatment inhibited protein synthesis in sensitive, but not resistant cell lines. In most cell lines, cell death seemed to be mediated by the “ribotoxic stress response.” This response involves activation of p38 MAPK and JNK/SAPK, and BLyS-gel mediated cytotoxicity was inhibited by the p38/JNK inhibitor SB203580. Finally, BLyS-gel treatment significantly prolonged survival in three distinct disseminated xenograft models (BCP-ALL, DLBCL & MCL) in SCID mice, and BLyS-gel was shown to specifically localize to sites of disease. Together, these findings suggest BLyS has potential as a targeting ligand for the therapeutic delivery of toxins and/or drugs directly to malignant B cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3861. doi:1538-7445.AM2012-3861

Clinical and Experimental Features of Natural Killer Cell Leukemias in a Chinese Population: A Single Center Experience of 10 Years

Abstract 4892Leukemia of natural killer (NK) cell lineage is rare which affects Asian population preferentially. Here 10 Chinese patients with NK cell leukemia were retrospectively evaluated. Among them 7 man and 3 women, the middle age was 47 years (range 22–57 years). Aggressive NK cell leukemias were finally diagnosed in 7 patients, myeloid/NK cell precursor acute leukemias in 2 patients and NK-CLPD in 1 patient. Pronounced extramedullary involvements (breast mass, multiple subcutaneous nodes and eye rectus muscle mass) were the main manifestation in 2 myeloid/NK cell precursor acute leukemias and 1 aggressive NK-cell leukemia. Clonal cytogenetic abnormality (46, XX, 16P-) was only found in 1 myeloid/NK cell precursor acute leukemia patient. Epstein-Barr virus test was performed in 8 patients and 3 were Positive (all were aggressive NK-cell leukemias). The overall survival of 4 cases of aggressive NK-cell leukemias combined with hematophagocytic syndrome were less than 1.3 months. During following up, 8 patients died of disease, 1 NK-CLPD patient and 1 aggressive NK-cell leukemia patient treated by allo-BMT were still alive. The former NK-CLPD, who was in indolent course, survived 60+ months. The later patient was first diagnosed as NK-CLPD but with lymphoadenopathy and splenomegaly, the metabolic activity of spleen by F-18 FDG uptake was in normal range, lymph node pathology showed reactive change and PB EBV-DNA copy was negative, later hematophagocytic syndrome occurred and EBV-DNA copy became positive. The lymph node pathology were reexamined by FISH method and scattered EBV positive cells were found, so the exact diagnosis from beginning should be occult aggressive NK cell leukemia, soon matched sibling donor BMT was performed and the patient got complete remission and the EBV-DNA copy became negative and lived well for 10+ months. Natural killer cell neoplasms are rare and most in aggressive clinical course, novel therapeutic regimens including allogeneic bone marrow transplantation should be investigated to improve outcome of this disease. Disclosures:No relevant conflicts of interest to declare.

皮膚浸潤が確認されたMyeloid/NK Cell Precursor Acute Leukemia

皮膚浸潤が確認されたMyeloid/NK Cell Precursor Acute Leukemia

Five Chinese Pediatric Patients with Leukemias Possibly Arising from Immature Natural Killer Cells: Clinical Features and Courses

Leukemias arising from immature nature killer (NK) cells have been proposed as distinct entities and are rare. Treatment and prognosis of these diseases are controversial, and data on children are limited. According to the literature, one of these distinct leukemias may be myeloid/NK cell precursor acute leukemia (MNKPL), with the blasts being cytochemically myeloperoxidase negative (MPO−) and phenotypically CD56+CD3−CD7+CD34+ and myeloid antigens+. The other may be myeloid/NK cell acute leukemia (MNKL), in which the blasts were cytochemically MPOdim and phenotypically CD56+CD16−CD3−CD33+HLA-DR−. Between 2005 and 2008, 4 MNKPL and 1 MNKL children aged 1.3 to 12.5 years were encountered in the First Affiliated Hospital of Sun Yat-Sen University. In those with MNKPL, remarkable extramedullary involvement usually occurring in adults was not observed; however, myelofibrosis was found in 2 children. The child with MNKL abandoned treatment. Those with MNKPL were treated with a protocol designed for childhood high-risk acute lymphoblastic leukemia (ALL) containing cytarabine, mitoxantrone, etoposide, l-asparaginase, and methotrexate according to the myeloid and lymphoid characteristics of MNKPL. They responded slowly to chemotherapy and were in complete remission (CR) for 26 to 63 months, except 1 who died in CR from pneumonia. They had longer survival and seemed to have a better outcome than those reported previously. In conclusion, childhood leukemias with immature NK cell markers may have different characteristics from their adult counterparts. A protocol including agents used for acute myeloid leukemia combined with those for ALL is seemingly effective for treatment of MNKPL. However, a modified treatment strategy designed more specifically for MNKPL and longer observations are needed.

NOTCH1 mutation in a female with myeloid/NK cell precursor acute leukemia

A 6-year-old Japanese female was diagnosed as having myeloid/NK cell precursor acute leukemia (MNKL) using immunocytochemical analysis. The patient was treated by cord blood transplantation from an HLA 1-locus mismatched unrelated donor after chemotherapy comprising cytosine arabinoside, idarubicin, etoposide, and L-asparaginase. We detected a nonsense mutation, C7412A, resulting in S2471X, where X is a terminal codon, in the PEST domain of NOTCH1 in this patient. The presence of the NOTCH1 activating mutation in MNKL might suggest a possible role in the leukemogenesis of MNKL.