Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a subtype of B-lineage ALL (B-ALL) that displays a gene expression profile (GEP) similar to Philadelphia chromosome-positive ALL (PhALL). It has a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, frequently accompanied by abnormal transcription factors related to lymphatic development. Children with Ph-like ALL account for 15% of children with high-risk B-ALL. It has adverse clinical features and a poor prognosis. Tyrosine kinase inhibitors combined with chemotherapy can significantly improve the prognosis of children with PhALL, suggesting that targeted therapy based on the molecular cytogenetic abnormalities of Ph-like ALL has good research prospects. This paper expounds the genetic alterations, pathogenesis, clinical features, diagnostic measures, and potential therapeutic approaches of Ph-like childhood ALL based on recent research progress in Ph-like ALL.
Humans ; Janus Kinase 2 ; genetics ; PAX5 Transcription Factor ; genetics ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; diagnosis ; drug therapy ; genetics ; Proto-Oncogene Proteins c-abl ; genetics

OBJECTIVEThe study was aimed to investigate the feasibility and clinical significance of quantitative detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) by real-time quantitative polymerase chain reaction (RQ-PCR).

METHODSClonal IgH gene rearrangements of samples at diagnosis were identified by standard PCR assay with consensus primers. Monoclonal IgH gene rearrangements were analyzed using DNAPLOT software. Upstream primers were designed with the Primer Express software and allele specific oligonucleotide developed complementary to the V-D or D-J junction. Samples at diagnosis were serially diluted to generate the patient specific standard curves. RQ-PCR method was used to quantify the MRD of the follow up samples collected at five time points during chemotherapy. To check the quantity and quality of DNA, the investigators used RQ-PCR analysis for the albumin gene.

RESULTSTotally 16 monoclonal IgH gene rearrangements were identified from 34 patients with B-ALL. The analysis of the 16 monoclonal rearrangements showed that the most frequently used V segment was from V3 family and J segment from J4 and J6. The RQ-PCR sensitivity of 10(-4) to 10(-5) was mostly reached. Non-specific amplification was seen in 6 patients. The number of inserted and deleted nucleotides did not appear to be related to the sensitivity (P > 0.05). The correlation coefficients of all 16 standard curves were excellent (> or = 0.99). The mean slope of the standard curves was -3.4 +/- 0.37 and the mean intercept was 24.3 +/- 2.95. MRD analysis of follow up samples from the 16 patients showed an association between high degree of MRD and relapse. There was no apparent relationship between MRD degree at the end of induction chemotherapy and other high risk factors of ALL (P > 0.05).

CONCLUSIONThe study showed that the above approach with RQ-PCR was applicable to clinical detection of MRD in childhood ALL. Quantitative and dynamic study of MRD was of prognostic importance.

Child ; Gene Rearrangement, B-Lymphocyte ; Humans ; Neoplasm, Residual ; diagnosis ; genetics ; Polymerase Chain Reaction ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; diagnosis ; drug therapy ; genetics ; Prognosis

CD4 Antigens ; metabolism ; CD56 Antigen ; metabolism ; Dendritic Cells ; pathology ; Diagnosis, Differential ; Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor ; Hematologic Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; surgery ; Humans ; Immunohistochemistry ; Leukemia, Myeloid ; pathology ; Lymphoma, Extranodal NK-T-Cell ; pathology ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; pathology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; pathology ; Skin Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; surgery

OBJECTIVETo study the clinical characteristics, risk factors and therapeutic outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia (Ph(+)aALL).

METHODSThe clinical data of 117 newly diagnosed adults with Ph(+)ALL in our hospital between January 1995 and December 2009 were retrospectively analyzed. And their prognoses were followed up.

RESULTSThere were 117(16.1%) of 727 aALL patients diagnosed as Ph(+)aALL. Among the 117 cases, 64.1% patients were classified as pre-B immunophenotype and 31.3% as common B immunophenotype, 37.5% patients with co-expression of myeloid antigens (CD13 or CD33), and 98.4% patients with positive CD34. The complete remission (CR) rate after 1 or 2 cycles of induction chemotherapy was 62.2% in Ph(+)aALL group versus 82% in Ph(-)aALL group (P = 0.000). The median disease-free survival time of Ph(+) group was 6 months and the median survival time was 9 months. Sole karyotype abnormality subgroup t(9;22) accounted for 53% of all Ph(+)aALL patients and additional karyotype abnormality subgroup, t(9;22) plus other chromosome variation, accounted for 47%. Patients in sole karyotype abnormality subgroup had slightly lower CR rate (59.6% vs 62.5%, P = 0.768), longer median survival time (7 months vs 4 months, P = 0.158), and higher 3-year overall survival rate (27.3% vs 14.4%, P = 0.271). For the myeloid antigen co-expressed patients and the only lymphocytic antigen expressed ones, CR rate was 56.0% and 61.5% (P = 0.750), the median survival time was 5 months and 4 months (P = 0.182), and the 3-year overall survival rate was 16.0% and 15.0% (P = 0.354), respectively. In the imatinib plus combination chemotherapy treatment group, 81.3% patients achieved CR, compared with that of 58.3% in patients treated with only traditional combination chemotherapy (P = 0.083). The median survival time was 9.5 months and 6 months (P = 0.003) in these two subgroup, and 3-year overall survival rate was 52.2% and 10.3% (P = 0.029), respectively. For the patients receiving allo-HSCT after CR and that receiving traditional consolidation chemotherapy, the median survival time was 15 months and 6 months (P = 0.000), and the 3-year overall survival rate was 62.0% and 10.3% (P = 0.000), respectively. For the patients receiving imatinib as consolidation-maintenance treatment and that receiving allo-HSCT, the median survival time was 12 months and 15 months (P = 0.300), and the 3-year overall survival rate was 64.7% and 62% (P = 0.505), respectively.

CONCLUSIONOf all adult ALL patients, the Ph(+) subgroup accounted for about 16.1%, which have unfavorable prognosis such as lower CR rate and shorter survival duration under traditional chemotherapy. Neither additional chromosome abnormalities to t(9;22) nor co-expression of myeloid antigen had negative effect on CR rate and survival duration. Addition of imatinib to the therapy was beneficial to improve the CR rate and survival duration. Either receiving imatinib as consolidation-maintenance treatment or allo-HSCT after complete remission can improve long-term survival rate of Ph(+) adult ALL group significantly.

Adult ; Benzamides ; Female ; Humans ; Imatinib Mesylate ; Male ; Philadelphia Chromosome ; Piperazines ; therapeutic use ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; diagnosis ; drug therapy ; genetics ; Prognosis ; Pyrimidines ; therapeutic use ; Retrospective Studies

This study was aimed to explore the relation between folylpolyglutamate synthetase (FPGS) rs10760502 polymorphism and prognosis and methotrexate (MTX)-related toxicities in pediatric B-cell acute lymphoblastic leukemia (B-ALL). Sequenom MassARRAY was used to genotype rs10760502. The χ(2) test, Kaplan-Meier method and Cox regression models were used to analyze the data. The results indicated that A allele carriers (GA+AA) had poor relapse free survival (RFS, log-rank: P = 0.004) and event free survival (EFS, log-rank: P = 0.022) compared with the GG genotype carriers. Multivariate Cox-regression analysis results showed that A allele is an independent prognosis factor for poor RFS [hazard ratio (HR), 20.173; 95% CI, 2.535-160.545; P = 0.005] and EFS (HR, 8.133; 95% CI, 1.718-38.512; P = 0.008). No relationship was found between any MTX toxicity and rs10760502 polymorphism. It is concluded that FPGS rs10760502G>A polymorphism may affect the treatment outcome of B-ALL patients.
Adolescent ; Child ; Child, Preschool ; Female ; Genotype ; Humans ; Infant ; Leukemia, B-Cell ; diagnosis ; drug therapy ; genetics ; Male ; Methotrexate ; adverse effects ; Peptide Synthases ; genetics ; Polymorphism, Genetic ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; Prognosis

Loss of heterozygosity (LOH) in chromosome 6p has been reported in a number of tumors and some hematologic malignancies, including ALL. LOH in chromosome 6p, on which the HLA genes are located, can give rise to false homozygosity results in HLA genotyping of patients with hematologic malignancies. Here we report false homozygosity results in HLA genotyping due to the loss of whole chromosome 6 in the neoplastic cells of a patient with ALL. A 33-yr-old Korean female patient was admitted for the evaluation of leukocytosis detected during a workup for headache. Her initial white blood cell count was 336.9x109/L with 84% of blasts in the differential count. Precursor-B lymphoblastic leukemia was diagnosed from a subsequent bone marrow study. HLA high-resolution genotyping of the patient was requested at the time of diagnosis for possible hematopoietic stem cell transplantation. Homozygosity results (A*02:01, B*54:01, C*08:01, DQB1*04:01) were obtained, except for the DRB1 locus (DRB1*04:05, DRB1*11:01), in sequence-based typing. Conventional karyotyping of bone marrow metaphase cells revealed chromosomal abnormalities, with loss of multiple chromosomes including chromosome 6, and reduplication of the remaining chromosomes: 29,X,+X,+8,inv(9)(p11q13),+10,+14,+18,+21[15]/58,idemX2[3]/46,XX,inv(9)[2]. LOH at the HLA region was suspected and HLA genotyping was repeated with the peripheral blood in remission state after induction chemotherapy. All 5 HLA loci were typed as heterozygous (A*02:01, A*02:06, B*40:01, B*54:01, C*03:04, C*08:01, DRB1*04:05, DRB1*11:01, DQB1*03:01, DQB1*04:01). To avoid false HLA typing results in patients with hematologic malignancies, clinicians, as well as laboratory personnel, need to be aware of such problems and take appropriate precautions.
Adult ; Chromosome Duplication ; *Chromosomes, Human, Pair 6 ; Diagnostic Errors ; Female ; Genotype ; HLA Antigens/*genetics ; Hematopoietic Stem Cell Transplantation ; Humans ; Karyotyping ; Leukocyte Count ; *Loss of Heterozygosity ; Nerve Tissue Proteins/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis/*genetics/therapy ; RNA-Binding Proteins/genetics

This study was aimed to analyze the clinical and cytogenetic characteristics of acute leukemia with 11q23/mll rearrangement and explore the reasonable therapeutic principles. Characteristics in general situation, morphology, immunology, molecular biology, cytogenetics, treatment and overall survival of 36 cases of acute leukemias with mll gene rearrangement were studied and analyzed. The results showed that 36 cases with mll gene rearrangement were found positive (7.2%) in 494 patients with acute leukemia. Among the 36 cases of mll rearrangement positive, 32 cases were diagnosed as acute myeloid leukemia (AML) with myeloid antigen expression, of which 5 cases expressed lymphoblastic differentiation antigen; 4 cases were classified as B-lineage acute lymphoblastic leukemia (ALL), of which non-lineage myeloid expression pattern were found in 3 cases. In 29 out of 36 cases (80%) the clonal chromosomal aberration were detected, of which chromosome 11 aberration were observed in 22 cases. All patients received chemotherapy with a total response rate of 47.2%. Of the responded patients, 10 cases relapsed within 6 months, with a recurrence rate of 40%; 9 cases received hematopoietic stem cell transplantation (HSCT), 7 cases of which survived after transplantation. The median survival time of 36 cases was 16 months (range 2 - 46) and their 2-year overall survival rate was 41.4%. The 2-year overall survival rate of 9 patients who received HSCT was 87.5%. It is concluded that acute leukemia patients with mll gene rearrangement show poor response to chemotherapy, high recurrence rate and poor prognosis. Hematopoietic stem cell transplantation may be a reasonable treatment principle to improve these patients' survival situation.
Adolescent ; Adult ; Aged ; Child ; Child, Preschool ; Female ; Hematopoietic Stem Cell Transplantation ; Histone-Lysine N-Methyltransferase ; Humans ; Infant ; Leukemia ; classification ; diagnosis ; genetics ; therapy ; Leukemia, Myeloid, Acute ; diagnosis ; genetics ; therapy ; Male ; Middle Aged ; Myeloid-Lymphoid Leukemia Protein ; genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; diagnosis ; genetics ; therapy ; Prognosis ; Survival Rate ; Young Adult

No abstract available.
Antineoplastic Agents/therapeutic use ; Base Sequence ; DNA/chemistry/genetics/metabolism ; DNA Mutational Analysis ; Fusion Proteins, bcr-abl/*genetics ; Genotype ; Humans ; Imatinib Mesylate/therapeutic use ; Karyotyping ; Male ; Multiplex Polymerase Chain Reaction ; Mutation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*diagnosis/drug therapy/*genetics

The translocation t(10;11)(p13;q14q21) has been found to be recurrent in acute lymphoblastic and myeloid leukemias, and results in the fusion of the clathrin assembly lymphoid myeloid leukemia (CALM) gene with the AF10 gene; these genes are present on chromosomes 11 and 10, respectively. Because the CALM-AF10 rearrangement is a rare chromosomal abnormality, it is not included in routine molecular tests for acute leukemia. Here, we describe the cases of 2 patients with the CALM-AF10 fusion gene. The first patient (case 1) was diagnosed with T-cell ALL, and the second patient (case 2) was diagnosed with AML. Both patient samples showed expression of the homeobox A gene cluster and the histone methyltransferase hDOT1L, which suggests that they mediate leukemic transformation in CALM-AF10-positive and mixed-lineage leukemia-AF10-positive leukemias. Both patients achieved complete remission after induction chemotherapy. The first patient (case 1) relapsed after double-unit cord blood transplantation; there was no evidence of relapse in the second patient (case 2) after allogenic peripheral blood stem cell transplantation. Since CALM-AF10- positive leukemias have been shown to have poor prognosis with conventional therapy, molecular tests for CALM-AF10 rearrangement would be necessary to detect minimal residual disease during follow-up.
Adolescent ; Adult ; Bone Marrow/pathology ; Chromosomes, Human, Pair 10 ; Chromosomes, Human, Pair 11 ; Cord Blood Stem Cell Transplantation ; Female ; Histone-Lysine N-Methyltransferase/genetics/metabolism ; Homeodomain Proteins/genetics/metabolism ; Humans ; Leukemia, Myeloid, Acute/diagnosis/*genetics/therapy ; Male ; Monomeric Clathrin Assembly Proteins/*genetics ; Oncogene Proteins, Fusion/*genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis/*genetics/therapy ; Recurrence ; Transcription Factors/*genetics ; Translocation, Genetic

This study was aimed to investigate the clinical features and therapy of Ph(+) acute lymphoblastic leukemia (Ph(+)ALL) combined with invasive aspergillosis. A series of examination, including routine blood and bone marrow picture analysis, chest roentgenography, cranial computerized tomography and detection of cell genetics etc were carried out for a Ph(+)ALL patient combined with invasive aspergillosis. This patient received chemotherapy with DVCP, idarubicin and imatinib mesylate and was treated with sporanox and amphotericin B (Amb; including Amb-L) and cerebrotomy for drainage because the invasive aspergillosis occurred during myelosuppression. The results showed that patient gained complete remission and the invasive aspergillosis was controlled successfully. It is concluded that patient with Ph(+)ALL has poor prognosis despite intensive conventional chemotherapy, imatinib mesylate may prove to be an effective treatment for Ph(+)ALL. Because detection rate of the fungus is very low, itraconazole in combination with surgical excision of focus is the best treatment of lung and brain invasive aspergillosis.
Antifungal Agents ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Aspergillosis ; diagnosis ; drug therapy ; Benzamides ; Brain Diseases ; complications ; microbiology ; Humans ; Imatinib Mesylate ; Itraconazole ; therapeutic use ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; complications ; Lung Diseases, Fungal ; drug therapy ; etiology ; Piperazines ; administration & dosage ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; complications ; genetics ; microbiology ; Pyrimidines ; administration & dosage