IgH and TCRgamma Gene Rearrangements, Cyclin A1 and HOXA9 Gene Expression in Biphenotypic Acute Leukemias.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4472-4472
Author(s):  
Mirna Golemovic ◽  
Mirna Sucic ◽  
Renata Zadro ◽  
Sanja Davidovic Mrsic ◽  
Mirta Mikulic ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
De Novo ◽  
Response To Treatment ◽  
Gene Rearrangements ◽  
In Vitro Growth ◽  
Chromosome 11 ◽  
Cyclin A1 ◽  
Rare Type ◽  
Acute Leukemias

Abstract Biphenotypic acute leukemia (BAL) represents a rare type of acute leukemia (AL) with the reported incidence of 4.0–8.5% and poor response to treatment. In adult BAL, poor prognosis is related to unfavorable cytogenetics and P-glycoprotein over-expression (Legrand et al, Br J Haematol1998;100:147–55). It is presumed that better knowledge of its biological features could improve the classification and clinical management of this rare type of acute leukemia. Due to paucity of data regarding biological parameters of BAL, in this study we have analyzed the rearrangements of immunoglobulin heavy chain (IgH) and T-cell receptor g (TCRg) genes, expression of cyclin A1 (CycA1) and HOXA9 genes as well as in vitro growth of 10 de novo BALs and compared them with 15 AML and 15 ALL, respectively. The diagnosis of BAL was established according to EGIL criteria. BAL represented 4.3% of adult and 3.0% of pediatric patients with de novo AL referred to our institution during the 1999–2003 period. Of 10 BALs studied, lymphoid BAL (L2) was identified in 3 children, myeloid BAL (M1 and M5) was identified in 3 adults and one child, BAL of undifferentiated cytomorphology (AUL) in 2 adult patients, whereas one 5-month-old child presented with two separate blast cell populations (L1+M5b, bilineal BAL). With regard to immunophenotype, the group of BAL patients was also heterogeneous: 8/10 expressed the combination of myeloid and B-lymphoid antigens and 2/10 expressed myeloid and T-lymphoid antigens. The majority of BAL expressed CD34 (89%). Cytogenetic analysis was obtained in 7 BAL patients, of whom 3 showed chromosome 11 aberrations and 1 had Ph+ chromosome. Our results indicate that IgH and TCRγ gene rearrangements correlated well with lymphoid BAL morphology. Interestingly, the majority of lymphoid BAL showed oligoclonal amplification of antigen-receptor genes, indicating the coexistence of several malignant clones at the time of presentation. The expression of CycA1 correlated well with myeloid and undifferentiated BAL morphology. In contrast, the expression of HOXA9, a marker associated with myeloid cell lineage, showed no strong correlation with BAL morphology. BAL showed almost equal in vitro growth in three different serum-free culture conditions (no addition of GF, addition of IL-7 and FL or GM-CSF and FL), indicating that their growth was less dependent on the addition of exogenous GFs. Finally, in vitro growth of blasts during a 7-day culture showed autonomous cell growth in 3/10 AML and 3/8 myeloid BAL samples tested, but not in any of the AL with lymphoid features. Finally, further studies are needed to confirm these findings and to extend research to a broader spectrum of cell markers aiming to give a better definition of this rare group of AL.

scholarly journals PIM2 and NF-κβ gene expression in a sample of AML and ALL Egyptian patients and its relevance to response to treatment

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shymaa Kamal El Din Abed El Rahman ◽  
Sanaa Sayed Abd Elshafy ◽  
Mohamed Samra ◽  
Hala Mohammed Ali ◽  
Rabab Afifi Mohamed
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Expression Level ◽  
Response To Treatment ◽  
Control Group ◽  
Poor Overall Survival ◽  
Healthy Control ◽  
Complete Blood Counts

Abstract Background The relation between PIM2 and the transcriptional factor NF κβ have been controversial in literature. The significance of PIM2 and NF-κβ genes expression on the incidence of acute leukemia (AML and ALL) and its relevance to the response rate was evaluated. Sixty de novo acute leukemia patients were stratified in 2 groups: 30 acute myeloid leukemia (AML) and 30 acute lymphoblastic leukemia (ALL) patients and compared to 30 sex- and age-matched controls. The expression level of PIM2 and NF κβ genes was measured using quantitative real-time polymerase chain reaction (QRT-PCR). The patients were followed with clinical examination and complete blood counts. Results The expression level of PIM2 gene was significantly higher in AML patients (P<0.001) compared to the control group. The mean expression level of NF κβ gene was significantly high in AML and ALL patients compared to the healthy control group (P=0.037 and P<0.001; respectively). The overall survival in AML patients was higher in NF κβ gene low expressers compared to high expressers (P=0.047). The number of AML patients who achieved complete remission was significantly higher in PIM2 gene low expressers in comparison to PIM2 gene high expressers (P=0.042). Conclusion PIM2 and NF κβ genes might have a role in the pathogenesis of acute leukemia, poor overall survival, and failure of response to induction therapy.

The Reliability and Specificity of c-kit for the Diagnosis of Acute Myeloid Leukemias and Undifferentiated Leukemias

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 596-599 ◽  
Author(s):  
M.C. Bene ◽  
M. Bernier ◽  
R.O. Casasnovas ◽  
G. Castoldi ◽  
W. Knapp ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
Specific Marker ◽  
Acute Leukemias ◽  
Routine Basis ◽  
Immunological Classification ◽  
B Lineage ◽  
Acute Myeloid

Abstract We document findings on c-kit (CD117) expression in 1,937 pediatric and adult de novo acute leukemia cases, diagnosed in five single European centers. All cases were well characterized as to the morphologic, cytochemical, and immunologic features, according to the European Group for the Immunological Classification of Leukemias (EGIL). The cases included 1,103 acute myeloid leukemia (AML), 819 acute lymphoblastic leukemia (ALL), 11 biphenotypic acute leukemia (BAL), and 4 undifferentiated (AUL). c-kit was expressed in 741 (67%) AML cases, regardless of the French-American-British (FAB) subtype, one third of BAL, all four AUL, but only in 34 (4%) of ALL cases. The minority of c-kit+ ALL cases were classified as: T-cell lineage (two thirds), mainly pro-T–ALL or T-I, and B lineage (one third); cells from 62% of these ALL cases coexpressed other myeloid markers (CD13, CD33, or both). There were no differences in the frequency of c-kit+ AML or ALL cases according to age being similar in the adult and pediatric groups. Our findings demonstrate that c-kit is a reliable and specific marker to detect leukemia cells committed to the myeloid lineage, and therefore should be included in a routine basis for the diagnosis of acute leukemias to demonstrate myeloid commitment of the blasts. c-kit expression should score higher, at least one point, in the system currently applied to the diagnosis of BAL, as its myeloid specificity is greater than CD13 and CD33. Findings in ALL and AUL suggest that c-kit identifies a subgroup of cases, which may correspond to leukemias either arising from early prothymocytes and/or early hematopoietic cells, both able to differentiate to the lymphoid and myeloid pathways.

In vitro growth of erythropoietic progenitor cells in long-term remission of acute leukemia

1986 ◽  
Vol 4 (3) ◽  
pp. 186-191 ◽  
Author(s):  
C. Peschel ◽  
G. Konwalinka ◽  
D. Geissler ◽  
H. Braunsteiner
Keyword(s):  
Acute Leukemia ◽  
Progenitor Cells ◽  
In Vitro Growth

scholarly journals Enrichment of Double RUNX1 Mutations in Acute Leukemias of Ambiguous Lineage

2021 ◽  
Vol 11 ◽  
Author(s):  
Gabriele Merati ◽  
Marianna Rossi ◽  
Anna Gallì ◽  
Elisa Roncoroni ◽  
Silvia Zibellini ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Genetic Basis ◽  
Lymphoblastic Leukemia ◽  
Gene Mutations ◽  
Rare Type ◽  
Acute Leukemias ◽  
Therapeutic Guidelines ◽  
Acute Myeloid

Acute leukemia of ambiguous lineage (ALAL) is a rare type of leukemia and represents an unmet clinical need. In fact, due to heterogeneity, substantial rarity and absence of clinical trials, there are no therapeutic guidelines available. We investigated the genetic basis of 10 cases of ALAL diagnosed at our centre from 2008 and 2020, through a targeted myeloid and lymphoid sequencing approach. We show that this rare group of acute leukemias is enriched in myeloid-gene mutations. In particular we found that RUNX1 mutations, which have been found double mutated in 40% of patients and tend to involve both alleles, are associated with an undifferentiated phenotype and with lineage ambiguity. Furthermore, because this feature is typical of acute myeloid leukemia with minimal differentiation, we believe that our data strengthen the idea that acute leukemia with ambiguous lineage, especially those with an undifferentiated phenotype, might be genetically more closer to acute myeloid leukemia rather than acute lymphoblastic leukemia. These data enrich the knowledge on the genetic basis of ALAL and could have clinical implications as an acute myeloid leukemia (AML) – oriented chemotherapeutic approach might be more appropriate.

scholarly journals Acute Megakaryocytic Leukemia (FAB M7)

1970 ◽  
Vol 20 (1) ◽  
pp. 89-92
Author(s):  
T Ara ◽  
MK Zaman ◽  
S Afrose ◽  
MS Islam ◽  
AR Biswas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Key Words ◽  
Peripheral Blood ◽  
De Novo ◽  
Supportive Therapy ◽  
Bone Marrow Examination ◽  
Rare Type ◽  
Acute Megakaryocytic Leukemia ◽  
Progressive Weakness

Acute megakaryocytic leukemia (AML M7) is a rare type of acute leukemia often presented with myelofibrosis.This report describes a 65 years old female who presented with progressive weakness and fatigue. She was diagnosed as a case of de novo AMLM-7 on the basis of peripheral blood finding, bone marrow examination report and immunophenotyping. She refused chemotherapy, received only supportive therapy and died after two months of diagnosis. Key Words: Acute megakaryocytic leukemia; thrombocytosis; immunophenotyping. DOI: http://dx.doi.org/10.3329/jdmc.v20i1.8590 J Dhaka Med Coll. 2011; 20(1) :89-92

In Vitro Growth Regulation and the Identification of Potential Signaling Pathways in T (4; 11), Pediatric Pre-B Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1896-1896
Author(s):  
Aru Narendran ◽  
Bijan Tijan ◽  
Lucas Coppes ◽  
Farrah Rhemtulah ◽  
Ron Anderson
Keyword(s):  
Signaling Pathways ◽  
Growth Regulation ◽  
Lymphoblastic Leukemia ◽  
Growth Stimulation ◽  
Cellular Growth ◽  
Leukemic Cells ◽  
Antibody Array ◽  
In Vitro Growth ◽  
Acute Leukemias

Abstract Among the various chromosomal translocations found in pediatric pre-B cell acute leukemias, the t (4; 11) group contains patients of all ages as well as a clustering of children at birth or in the first year of life. As with all 11q23 abnormalities, t (4; 11) fusion confers an extremely poor prognosis. Using cell lines, many recent studies have described important molecular and cellular growth properties of these cells. We have investigated in vitro growth regulation of freshly isolated infant pre-B ALL cells with t (4; 11). Leukemic blasts were affinity purified with anti CD19 antibodies and cultured in the presence of various cytokines including IL-3, IL-1, FLT-3 ligand (FL), SCF, IL-6, IL-7, GM-CSF, PDGF, SDF-1, VEGF, EPO and GCSF. Cell proliferation after four days in culture was quantified by Alamar blue assay. At pg/ ml concentrations, significant growth stimulation was seen in the presence of FL and IL-7. The FLT-3 effect was much less prominent against leukemic cells without t (4; 11). Then we aimed to identify the possible signaling pathways utilized by the FLT-3 mediated stimulation of these cells. Purified blasts were cultured in serum free medium for 24 hours and stimulated for 0, 5 and 10 minutes with 10 pg/ml of FL. These cells were subsequently lysed and total cellular extracts were analyzed by an antibody array technique. The arrays used consisted of antibodies against a selection of fifty proteins involved in all known signaling pathways. Changes in the amount of phosphorylated proteins following FL treatment were identified by enzyme conjugated anti phospho specific antibodies. A number of reproducible FL specific changes were observed. These include increased Ets-1/2, JNK1, 2,3, p38MAPK and Src. We describe the detail analysis of the signaling pathways potentially utilized by these cells and illustrate the use of this experimental approach to identify possible targeted therapeutic agents against this particular form of leukemia.

Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 586-592 ◽  
Author(s):  
JP Marie ◽  
R Zittoun ◽  
BI Sikic
Keyword(s):  
Gene Expression ◽  
Multidrug Resistance ◽  
Complete Remission ◽  
Acute Leukemia ◽  
Remission Rate ◽  
Leukemia Cells ◽  
Acute Leukemias ◽  
Mdr1 Gene Expression ◽  
Mdr1 Expression

Resistance to multiple chemotherapeutic agents has been related to the production of P-glycoprotein, a trans-membrane drug efflux pump that is encoded by the multidrug resistance (MDR) gene mdr1. To investigate whether mdr1 could be involved in clinical resistance to chemotherapy in acute leukemias, we have analyzed retrospectively the RNA from adult acute leukemia cells by slot-blot hybridization with a human mdr1 probe. Units of mdr1 expression were defined by reference to drug- sensitive human sarcoma and K562 leukemia cell lines (1 U) and the highly resistant doxorubicin selected leukemia cells K562/R7 (50 U). We studied 41 adult patients with acute leukemias: 5 acute lymphoblastic leukemias, 23 acute myeloid leukemias, and 13 secondary leukemias or blast crisis of chronic myelogenous leukemia. Expression of 10 U or more of mdr1 was found in 6 of 31 (19%) leukemias at diagnosis, versus 5 of 10 (50%) after relapse from therapy, P = .06. The complete remission rate and in vitro sensitivity to daunorubicin were both correlated with low expression (1 U, v 2 U or more) of mdr1. Among 36 evaluable attempts to induce remission, the complete remission rate was 67% (8 of 12) for patients with undetectable or minimal mdr1 expression (1 U), versus 29% (7 of 24) in patients with 2 U or more of expression, P = .03. In vitro resistance to daunorubicin or other MDR-related drugs was associated with expression of 2 U or more of mdr1 in 11 of 11 cases, while specimens that were sensitive to these agents were negative for mdr1 expression in 5 of 11 cases, P = .03. These data suggest that mdr1 expression contributes to chemoresistance in acute leukemia. Determination of mdr1 gene expression may be useful in designing therapy for patients with leukemia.

scholarly journals Application of the AMLprofiler Diagnostic Microarray in the South African Setting

2017 ◽  
Vol 2017 ◽  
pp. 1-8
Author(s):  
S. S. Kappala ◽  
M. Alessandrini ◽  
T. Matlhako ◽  
E. Beltchev ◽  
R. Pool ◽  
...  
Keyword(s):  
South Africa ◽  
Bone Marrow ◽  
South African ◽  
De Novo ◽  
Survival Rates ◽  
Gene Profiling ◽  
Response To Treatment ◽  
Altered Expression ◽  
De Novo Aml

Acute myeloid leukemia (AML) is characterized by proliferation of the myeloid lineage and accumulation of immature hematopoietic cells in the bone marrow and is typified by marked heterogeneity both in response to treatment and survival. AMLprofiler is a qualitative in vitro diagnostic microarray incorporating seven molecular biomarkers used to diagnose and predict posttherapy survival rates. In this study, we compared AMLprofiler to routine AML diagnostic methodologies employed in South Africa, focusing on consistency of the results, cost, and time to result. RNA was isolated from bone marrow and peripheral blood samples from patients with de novo AML and was processed using Affymetrix Gene Profiling Reagent kits. The results from AMLprofiler and standard methodologies were highly comparable. In addition, many samples were determined to be positive for biomarkers not routinely investigated in South Africa, namely, CEBPA double mutants, NPM1 variants, and altered expression levels of BAALC and EVI1. 38% of samples presented with no positive biomarker; AMLprofiler nonetheless enabled 26% of AML patients to be classified into either favorable or poor prognostic categories. This study highlights the comprehensive nature of the microarray. Decreased time to result and refinement of risk stratification are notable benefits.

scholarly journals Acute leukemia after a primary myelodysplastic syndrome: immunophenotypic, genotypic, and clinical characteristics [see comments]

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 768-774
Author(s):  
JF San Miguel ◽  
JM Hernandez ◽  
R Gonzalez-Sarmiento ◽  
M Gonzalez ◽  
I Sanchez ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myelodysplastic Syndrome ◽  
Molecular Genetic ◽  
Cell Receptor ◽  
Chain Gene ◽  
Gene Rearrangements ◽  
Acute Leukemias ◽  
Cell Components ◽  
Blast Cells ◽  
Multiparameter Analysis

We studied the nature of blast cells in 41 patients with acute leukemia following a previous primary myelodysplastic syndrome (MDS) by a combined multiparameter analysis including morphologic, immunophenotypic, and molecular genetic (Igs, T-cell receptor (TCR)- beta, -gamma, and -delta and the major breakpoint cluster region [M- bcr]) investigations. In addition, the clinical and hematologic characteristics according to the immunophenotype of blast cells were analyzed. Our results show that, although the granulocytic and/or monocytic lineages are those most commonly involved in these acute leukemias, other cell components, including the megakaryocytic and lymphoid, may be present (12% and 15% of the cases, respectively). Moreover, both morphologic and phenotypic studies show the frequent coexistence of two or three cell populations. Interestingly, in all cases the lymphoblastic component constantly displayed an early B phenotype (CD19+, CD10-, TdT+). Upon analyzing whether the type of MDS conditioned any differences in the immunophenotype of blast cells, we observed that, although the lymphoid lineage may be involved in all MDS subgroups, some differences emerge within the myeloid leukemic transformations. Thus, the refractory anemias with excess of blasts (RAEB) and RAEB in transformation displayed a significantly higher incidence of myeloblastic and megakaryoblastic transformations, while in the RA, RA with ring sideroblasts and chronic myelomonocytic leukemia, the granulo-monocytic phenotype predominated. In addition, our results show that the clinical and hematologic characteristics of these patients may be partially related to the immunophenotype of the blast cells. Ig heavy chain gene rearrangements were found in two of 19 patients analyzed (11%), one with a hybrid leukemia (lymphoid-myeloid) and the other with a granulo-monocytic phenotype. Two other hybrid transformations analyzed were in germline configuration. Gamma and delta gene rearrangements were found in 21% and 37% of these acute transformation, respectively. The TCR-beta and M-bcr were in germline configuration in all 19 cases studied. In summary, immunophenotype and molecular studies point to a pluripotent stem cell with preferential myeloid commitment as the target cell of leukemias following a primary MDS.

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