KMT2A-ARHGEF12, a Therapy Related Fusion with Dismal Prognosis.

2021 ◽  
Author(s):  
Nada Assaf ◽  
Raphael Liévin ◽  
Fatiha Merabet ◽  
Victoria Raggueneau ◽  
Jenifer Osman ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Risk Stratification ◽  
Gene Rearrangements ◽  
Biological Mechanism ◽  
Chromosome 11 ◽  
Reciprocal Translocations ◽  
Acute Leukemias ◽  
Dismal Prognosis ◽  
Hematologic Neoplasm ◽  
Clinical Consequences

Abstract Background: The detection of KMT2A gene rearrangements have an important impact on the prognosis and management of acute leukemias. These alterations most commonly involve reciprocal translocations at specific breakpoint regions within KMT2A. To date, more than 100 translocation partner genes of KMT2A have been identified, with different effects on risk stratification. Methods and Results: We report the case of a mature plasmacytoid dendritic cells proliferation associated with B lymphoblasts harboring a KMT2A-ARHGEF12 fusion. This rare rearrangement, resulting from a cryptic deletion on the long arm of chromosome 11, is located outside the known major and minor breakpoint regions of KMT2A, not reported to date. The review of the few cases of KMT2A-ARHGEF12 reveals the tendency of this deletion to occur in therapy related hematologic neoplasm and confer unfavorable prognosis. Conclusion: This review sheds light into the rare KMT2A-ARHGEF12 fusion in leukemia. Reporting rare chimeras is essential to improve knowledge about the biological mechanism and associated clinical consequences.

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 K-ras mutations and N-ras mutations in childhood acute leukemias with or without mixed-lineage leukemia gene rearrangements

Cancer ◽  
2006 ◽  
Vol 106 (4) ◽  
pp. 950-956 ◽  
Author(s):  
Der-Cherng Liang ◽  
Lee-Yung Shih ◽  
Jen-Fen Fu ◽  
Huei-Ying Li ◽  
Hsiu-I Wang ◽  
...  
Keyword(s):  
Mixed Lineage Leukemia ◽  
Gene Rearrangements ◽  
Acute Leukemias ◽  
Ras Mutations

Absolute Lymphocyte Count Is a Novel Prognostic Indicator in Acute Leukemia: Implications for Risk Stratification and Future Studies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2276-2276
Author(s):  
Guillermo R. De Angulo ◽  
Carrie Yuen ◽  
Shana Palla ◽  
Peter M. Anderson ◽  
Patrick A. Zweidler-McKay
Keyword(s):  
Bone Marrow ◽  
Young Adults ◽  
Multivariate Analysis ◽  
Risk Stratification ◽  
Acute Leukemia ◽  
Induction Therapy ◽  
Age At Diagnosis ◽  
Acute Leukemias ◽  
Children And Young Adults ◽  
Current Risk

Abstract Background: Despite improving outcomes, 25–50% of children and young adults with acute leukemia still relapse and most salvage rates are discouraging. Additional prognostic factors, particularly those that represent host factors, may further stratify patients and decrease relapse rates. Purpose: To determine if absolute lymphocyte counts (ALC) during induction chemotherapy can improve current risk stratification and predict relapse-free survival (RFS) and overall survival (OS) in children and young adults with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Methods: We analyzed 160 consecutive cases of de novo ALL and AML patients 1–21 years of age, treated at the University of Texas M. D. Anderson Cancer Center from 1995–2005. Age at diagnosis, initial WBC, bone marrow blast % on days 0 and 7, were analyzed with ALC on days 0, 15, 21 and 28 of induction therapy. Results: ALC during induction therapy is a significant independent predictor of RFS and OS in young adults and children with either ALL or AML. Specifically, an ALC <350 cells/mcL on day 15 of induction therapy for ALL significantly predicts poor 6-year OS (52% vs. 87%, p=0.015; HR=4.2, Figure 1A) and RFS (46% vs. 80%, p=0.001; HR=4.8, Figure 1B). Similarly, an ALC of <350 cells/mcL on day 15 of induction therapy for AML predicts poor 6-year OS (35% vs. 86%, p=0.033; HR=4, Figure 1C). ALC-15 remains a significant predictor of OS and RFS after adjusting for age at diagnosis, initial WBC and bone marrow response on day 7 (p=0.013; HR=6.3, and p=0.003; HR=6.3, respectively) in multivariate analysis (Table 1). Importantly, ALC-15 defines a subgroup of half of our AML patients and predicts an excellent 5-year OS of 86% (p=0.033, Figure 1C). Conversely, prolonged lymphopenia predicts that 16% of young AML patients will have a dismal 5-year RFS of 14% (p=0.004, Figure 1D). Finally, ALC-15 <350 cells/mcL is able to predict 70% of relapses in both ALL and AML patients. One possible algorithm could identify half of AML patients with a predicted OS of 86% simply by measuring the ALC-15. Those patients with a low ALC on day 15 would be assessed at day 21 and 28 and those with persistent lymphopenia would be predicted to to have an RFS of 14% and would be stratified to receive intensified and/or experimental therapy. Conclusion: We demonstrate that ALC can identify patients at high and low risk for relapse early in the course of treatment for ALL or AML. Our data indicates that ALC is both independent of and a more powerful predictor than age at diagnosis, initial WBC and bone marrow response on day 7. This routine measurement could enhance current risk-stratification and lead to improved outcomes in young patients with acute leukemias. Figure 1 Figure 1. Table 1 Multivariate Analysis of ALC, Age, WBC, Bone marrow response and Survival

CALM-AF10 Positive T-ALLs Show a Pattern of Expression Similar to MLL-Translocated Acute Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1108-1108
Author(s):  
Eric Delabesse ◽  
Wim A. Dik ◽  
Wajih Brahim ◽  
Charlene Braun ◽  
Vahid Asnafi ◽  
...  
Keyword(s):  
Hox Genes ◽  
Fusion Gene ◽  
Insertion Site ◽  
Homeobox Gene ◽  
Chromosome 11 ◽  
Acute Leukemias ◽  
Bmi1 Expression ◽  
Independent Analysis ◽  
Genes Expression ◽  
Therapeutic Protocols

Abstract The t(10;11) translocation is recurrent in T-ALL and AML. The AF10 gene on chromosome 10 is rearranged either with MLL or CALM located on chromosome 11. CALM-AF10 fusion gene is found in T-ALLs in immature (IM) and TCRγδ-expressing (TCRGD+) T-ALLs. We compared 6 CALM-AF10+ T-ALLs cases (4 IM, 2 TCRGD+) to 17 CALM-AF10 negative T-ALLs cases (14 IM, 3 TCRGD+) using Affymetrix U133A microarrays. 44 genes were significantly overexpressed in CALM-AF10+ T-ALLs, the most significant being HOXA9, a homeobox gene overexpressed in MLL-translocated acute leukemias (MLL-t AL), BMI1, a polycomb family member whose function in regulation of HOX genes expression is opposite to Trithorax genes (whose MLL belongs), SOX4, a frequent insertion site in retroviral-induced leukemogenesis, SFRS6 and COMMD3 (p≤0.001). Only two other HOX genes, HOXA5 and HOXA10, were significantly increased. 89 genes were significantly underexpressed in CALM-AF10+ T-ALLs, the most significant being GGH, ARL6IP4, NBS1, OGFR and TUBB (p≤0.001). An independent analysis of the expression of HOXA5, HOXA9, HOXA10 and BMI1 genes was done by quantitative RT-PCR in 10 CALM-AF10+ T-ALLs and 27 CALM-AF10 negative T-ALLs. These were compared to 19 MLL-translocated acute leukemias (2 MLL-AF10, 5 MLL-AF4, 3 MLL-AF6, 5 MLL-AF9, 3 MLL-ELL and 1 MLL-ENL), since HOXA9 overexpression had been previously associated with MLL-t AL. HOXA5, HOXA9 and HOXA10 expression were higher in CALM-AF10+ T-ALLs than in CALM-AF10 negative T-ALLs (p&lt;0.001), confirming the microarray results. HOXA5 and HOXA9 expressions in CALM-AF10+ T-ALLs were similar to those detected in MLL-t AL and lower for HOXA10 in CALM-AF10+ T-ALLs as compared to the values of MLL-t AL (p=0.008). BMI1 expression in CALM-AF10+ T-ALLs was significantly higher than in CALM-AF10 negative T-ALLs and MLL-t AL (p&lt;0.001). Additionally, MEIS1 expression was determined as this gene was associated in MLL-t AL with the overexpression of HOXA9. As for BMI1, MEIS1 expression was significantly higher in CALM-AF10+ T-ALLs compared to CALM-AF10 negative T-ALLs and MLL-t AL (p&lt;0.001 and p=0.019, respectively). In summary, we demonstrated here the association between CALM-AF10 in T-ALLs and overexpression of HOXA5, HOXA9, HOXA10, BMI1 and MEIS1 genes. Overexpression of BMI1 is restricted to CALM-AF10+ T-ALLs. Although no obvious similarities are apparent between MLL and CALM proteins, the activation of HOXA and MEIS1 genes represent a highly recurrent pattern of expression in CALM-AF10+ T-ALLs and MLL-t AL. Consequently, the leukemias resulting in the activation of HOXA9 (MLL-t AL, CALM-AF10+ AL, NUP98-HOXA9 AML) should be seen as an independent group of acute leukemias and may benefit from common therapeutic protocols.

Acute Myeloid Leukemia (AML-M2) with a Novel Translocation t(5;11)(q35;q13) and Normal Expression of Cyclin D1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4538-4538
Author(s):  
Fabio M. de Oliveira ◽  
Guilherme A.S. dos Santos ◽  
Andre F. Marinato ◽  
Amelia G. Araujo ◽  
Ana S.G. Lima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cyclin D1 ◽  
Genetic Alterations ◽  
Myelogenous Leukemia ◽  
Benign Tumors ◽  
Renal Oncocytoma ◽  
Chromosome 11 ◽  
Acute Leukemias ◽  
Classical Cytogenetics ◽  
Marrow Cells

Abstract Rearrangements of the long arm of chromosome 11 are commonly associated with acute leukemias, with the breakpoints clustered mainly to the 11q23 region, frequently leading to the rearrangement of the MLL gene. CCND1 (previously PRAD1, BCL1), the gene encoding cyclin D1, is located at 11q13. Overexpression of cyclin D1 represents one of the common genetic alterations in human neoplasia, leading to a change in G1-S transition and uncontrolled cell growth. Here we describe the case of a patient with acute myelogenous leukemia (AML) harboring a chromosomal translocation involving 11q13 and a new partner, chromosome 5. A 30-year-old male presented with dyspnea for one month and peripheral blood counts of: hemoglobin 4.9 g/dL, platelets 62 x 109/L and leukocytes 29.5 x 109/L (with 45% of blasts). Bone marrow examination showed a hypercellular marrow with 82% blasts positive for myeloperoxidase and negative for non-specific esterase. The case was classified as AML M2 according to FAB. Classical cytogenetics and spectral karyotyping (SKY) studies performed by unsynchronized culture of the marrow cells revealed an abnormal clone of 46,XY, t(5;11)(q35;q13)[20]. RT-PCR for the rearrangements MLL/AF9, MLL/AF6, MLL/AF4, MLL/ENL, and MLL/ELL were performed and were negative for all of them. Cyclin D1 overexpression was not detected in bone marrow cells by Real Time PCR. The patient was submitted to induction chemotherapy with Daunorrubicin and Cytarabine but obtained only partial remission after 2 cycles of chemotherapy (10% of blasts in bone marrow after second induction). He was than submitted to an allogeneic stem cell transplantation (SCT) from his HLA identical sister. On day +30 after SCT he was in complete hematological remission. The classical cytogenetics study after chemotherapy and bone marrow transplantation revealed karyotypes 46,XY[20] and 46,XX[15]/46,XY[15]chi, respectively. The t(5;11)(q35;q13) represents a recurrent abnormality in renal oncocytoma (benign tumors that occur predominantly in the kidney) and leads frequently to cyclin D1 overexpression. Nevertheless, this cromossomal translocation has never been described in AML.

Environmental Factors Determine Lineage Fate in a Human Model of MLL-AF9 Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3374-3374
Author(s):  
Junping Wei ◽  
Wunderlich Mark ◽  
Catherine Fox ◽  
Jorge F. DiMartino ◽  
James C. Mulloy
Keyword(s):  
Fusion Gene ◽  
Human Model ◽  
Fusion Partner ◽  
Reciprocal Translocations ◽  
Acute Leukemias ◽  
Human Cd34 ◽  
B Lymphoid ◽  
Novel Therapeutic Strategies

Abstract The MLL gene is fused to over 30 different fusion partners by reciprocal translocations in human acute leukemias. Some fusion partners are associated almost exclusively with myeloid or lymphoid leukemias while others are found in both. The degree to which the fusion partner contributes to the lineage of the resulting leukemia remains a matter of controversy. Using a novel model system, we demonstrate that myeloid vs lymphoid differentiation of hematopoietic progenitors transformed by MLL-AF9 can be predictably driven by cytokine combinations in vitro and in vivo. The t(9;11)(p22;q23) MLL-AF9 fusion gene is commonly associated with M5 myeloid leukemia but approximately 5% of MLL-AF9 leukemia is B-lymphoid. Expression of MLL-AF9 in human CD34+ cells enables efficient modeling of acute myeloid, B-lymphoid and biphenotypic leukemia. The lineage of the resulting leukemia can be readily manipulated in vitro (by altering the growth factors) or in vivo (using B-lymphoid-biased NOD/SCID mice or myeloid-biased NOD/SCID that are transgenic for human SCF, GM-CSF and IL-3). The cytokines IL-3, IL-7 and FLT3L appear to exert the major effects on lineage fate determination in vitro. Through limiting dilution and clonality analyses, we find a complex relationship between different leukemia stem cell compartments, with some LSC demonstrating multipotentiality and others showing strict lineage commitment. Data indicate that these differences are primarily due to microenvironment effects, with the identity of the initial cell that is targeted by MLL-AF9 possibly playing a role. These results would argue against a deterministic role for the fusion partner in MLL leukemia. This human-based system should prove useful in addressing the mechanism of lineage promiscuity of MLL leukemias. It also affords us the unique ability to determine the susceptibility of the different LSC to standard chemotherapeutic compounds, in addition to identifying novel therapeutic strategies that may be effective in treating MLL leukemia.

scholarly journals What drives success in models predicting heart failure outcome?

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Gutman ◽  
U Shalit ◽  
O Caspi ◽  
D Aronson
Keyword(s):  
Heart Failure ◽  
Risk Stratification ◽  
Prediction Models ◽  
Cox Model ◽  
Prediction Method ◽  
Patient Specific ◽  
Funding Source ◽  
Therapy Regimen ◽  
Dismal Prognosis ◽  
Multiple Covariates

Abstract Introduction The development of acute heart failure (AHF) is a critical decision-point in the natural history of heart failure and carries a dismal prognosis. The lack of appropriate risk-stratification tools for AHF patients limits physician ability to precisely tailor patient-specific therapy regimen at this important juncture. Machine learning (ML) based strategies may enhance risk stratification by incorporating analysis of high-dimensional patient data with multiple covariates and novel prediction methodologies. In this study, we aimed at evaluating the drivers for success in prediction models and establishing an institute-tailored ML-based prediction model for real-time decision support. Methods We used a cohort of all AHF patients admitted during a 12 years period including 10,868 patients. A total of 372 covariates were collected from admission to the end of the hospitalization (demographics, lab-tests, medical therapies, echocardiographic and administrative data). Data preprocessing included features cleaning, train-test split, imputation and normalization. We assessed model performance across two axes (1) type of prediction method and (2) type and number of covariates. The primary outcome was one-year survival from hospital discharge. For the model-type axis we experimented with seven different methods: Logistic Regression (LR), Random Forest (RF), Cox model (Cox), XGBoost, a deep neural-network (NeuralNet) and an ensembled model. Results Data pre-processing methodology combined with multiple-covariates achieved an out-ofsample AUROC prediction accuracy of more than 80% with almost all prediction models: L1/L2-LR (80.4%/80.3%); Cox (80.1%); XGBoost (80.7%); NeuralNet (80.5%). The number of covariates was a significant modifier of prediction success (p&lt;0.001), the use of multiple-covariates (372) performed better (AUROC 80.4% for L1-LR) compared with using only a set of known clinical covariates (AUROC 77.8%). Conclusions The choice of the predictive modeling method is secondary to the multiplicity and type of covariates for predicting AHF prognosis. The application of a structured data pre-processing combined with the use of multiple-covariates results in an accurate, institute-tailored, risk prediction in AHF. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Yad Hanadiv

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