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

scholarly journals HOXA9 is required for survival in human MLL-rearranged acute leukemias

Blood ◽  
2009 ◽  
Vol 113 (11) ◽  
pp. 2375-2385 ◽  
Author(s):  
Joerg Faber ◽  
Andrei V. Krivtsov ◽  
Matthew C. Stubbs ◽  
Renee Wright ◽  
Tina N. Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiling ◽  
Therapeutic Option ◽  
Mixed Lineage Leukemia ◽  
High Level Expression ◽  
Acute Leukemias ◽  
Gene Expression Analyses ◽  
High Level ◽  
Novel Therapeutic

Leukemias that harbor translocations involving the mixed lineage leukemia gene (MLL) possess unique biologic characteristics and often have an unfavorable prognosis. Gene expression analyses demonstrate a distinct profile for MLL-rearranged leukemias with consistent high-level expression of select Homeobox genes, including HOXA9. Here, we investigated the effects of HOXA9 suppression in MLL-rearranged and MLL-germline leukemias using RNA interference. Gene expression profiling after HOXA9 suppression demonstrated co–down-regulation of a program highly expressed in human MLL-AML and murine MLL-leukemia stem cells, including HOXA10, MEIS1, PBX3, and MEF2C. We demonstrate that HOXA9 depletion in 17 human AML/ALL cell lines (7 MLL-rearranged, 10 MLL-germline) induces proliferation arrest and apoptosis specifically in MLL-rearranged cells (P = .007). Similarly, assessment of primary AMLs demonstrated that HOXA9 suppression induces apoptosis to a greater extent in MLL-rearranged samples (P = .01). Moreover, mice transplanted with HOXA9-depleted t(4;11) SEMK2 cells revealed a significantly lower leukemia burden, thus identifying a role for HOXA9 in leukemia survival in vivo. Our data indicate an important role for HOXA9 in human MLL-rearranged leukemias and suggest that targeting HOXA9 or downstream programs may be a novel therapeutic option.

Childhood Mixed Lineage Leukemia: The St. Jude Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1844-1844
Author(s):  
Mihaela Onciu ◽  
Ching-Hon Pui ◽  
Fred G. Behm ◽  
Bassem I. Razzouk ◽  
Raul C. Ribeiro ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Induction Therapy ◽  
Therapeutic Approach ◽  
Pediatric Patients ◽  
Response To Therapy ◽  
Mixed Lineage Leukemia ◽  
Remission Induction ◽  
Acute Leukemias ◽  
Term Survival

Abstract PURPOSE: To report a single institutional experience with presenting features, therapeutic approach and outcomes in pediatric mixed lineage acute leukemias, as defined by the WHO classification (including biphenotypic, bilineal and poorly differentiated leukemias). PATIENTS AND METHODS: Retrospective study of all pediatric patients with acute leukemias fulfilling the EGIL/WHO criteria for mixed-lineage leukemia, treated at St. Jude Children’s Research Hospital from 1985–2006. Features analyzed included morphology, cytochemistry, immunophenotype (flow cytometry), cytogenetics, therapy, response to therapy (including minimal residual disease level as detected by flow cytometry) and outcome. RESULTS: Of 1500 patients with newly diagnosed acute leukemia, 35 (21 boys and 14 girls), were diagnosed to have mixed lineage leukemia. They ranged in age between 2 days and 19 years (median, 10 years) and had a median leukocyte count of 18 × 109/L (range, 1 to 150 × 109/L). Morphologic and flow cytometric studies identified these leukemias as biphenotypic T-lymphoid/myeloid (20 cases), B-lymphoid/myeloid (10 cases), B/T-lymphoid/myeloid (2 cases), bilineal (2 cases) and undifferentiated (1 case). Sixteen cases showed cytochemical positivity for myeloperoxidase (1% to 90%, median 5%) and 9 cases had Auer rods. Twenty-three patients initially received standard induction therapy for AML (cytarabine, daunorubicin, and etoposide) and 12 patients received ALL-directed remission induction [prednisone, vincristine, L-asparaginase (PVA), and daunomycin]. Of the former group, 12 (52%) achieved complete remission (CR), 2 attained partial remission (PR), 8 had no response (NR), and 1 died of toxicity. Ten of the 12 patients (83%) who first received ALL therapy achieved CR and only 2 had NR. Thus, after initial induction therapy, 22 of the 35 patients (63%) achieved CR. However, 8 of the 10 patients who had NR or PR to AML therapy attained CR after receiving standard ALL induction therapy with only PVA, and 1 of 2 patients who had NR to ALL therapy achieved CR after receiving AML therapy, resulting in an overall CR rate of 91% (32 of 35 patients). Notably, of the 8 patients who did not respond to AML therapy but achieved CR after PVA, all 4 tested were MRD-negative after PVA and all 6 who received multiagent chemotherapy without transplantation are alive and in long-term remission for 1.1 to 16.4 years. Seven of these 8 patients had T-lymphoid/myeloid biphenotypic leukemia with expression of CD2, CD7, cytoplasmic CD3, and low MPO positivity (1% to 3.5%). Overall, among patients who achieved CR, 15 of 20 patients treated with chemotherapy alone are alive in remission, compared to only 4 of 11 patients who underwent transplantation. CONCLUSIONS: Pediatric patients with mixed lineage leukemia may benefit from a therapeutic approach directed against both AML and ALL. We suggest that patients who respond well to myeloid-directed therapy should continue to receive this therapy, whereas those who require lymphoid-directed induction should receive prolonged continuation treatment directed against both ALL and AML. Furthermore, our results indicate that patients with mixed lineage leukemias who achieve remission do not require stem cell transplantation to achieve long term survival.

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.

K-Ras Mutations and N-Ras Mutations in Childhood Acute Leukemias with and without MLL Rearrangements.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2851-2851
Author(s):  
Der-Cherng Liang ◽  
Lee-Yung Shih ◽  
Chang-Liang Lai ◽  
Tung-Huei Lin ◽  
Jen-Fen Fu ◽  
...  
Keyword(s):  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Leukemic Cells ◽  
Rt Pcr ◽  
Acute Leukemias ◽  
Ras Mutations ◽  
Fusion Transcripts ◽  
Ras Genes ◽  
De Novo Aml

Abstract BACKGROUND. Ras mutations are thought to drive proliferation of leukemic cells. We sought to determine the frequency of N-Ras and K-Ras mutations in a large cohort of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) with special reference to the presence or absence of MLL gene rearrangements. METHODS. Bone marrow samples from 300 children with B-precursor ALL, and 132 children with de novo AML were studied at initial diagnosis. Southern blot analysis was performed to detect MLL rearrangement. RT-PCR was used to detect common MLL fusion transcripts. cDNA panhandle PCR technology was used to identify the infrequent or unknown MLL partner genes. DNA PCR or RT-PCR followed by direct sequencing for each PCR product was performed to detect mutations at codons 12, 13 and 61 of N-Ras and K-Ras genes. RESULTS. Of the 300 patients with B-precursor ALL, 20 had MLL(+), the MLL fusion transcripts included 10 MLL-AF4, 7 MLL-ENL, 2 MLL-AF9, and 1 MLL-AF10, all had pro-B subtype (with CD10 negative). Of the 132 patients with de novo AML, 16 had MLL(+), including 4 MLL-AF9, 5 MLL-AF10, 2 MLL-ENL, one each of MLL-AF1, MLL-AF4, MLL-ELL, MLL-SEPT6 and MLL-PTD. N-Ras mutations were detected in 2 of 20 MLL(+) ALL and in 26 of 274 MLL(−) ALL patients (P=1.000). N-Ras mutations were detected in 2 of 16 MLL(+) AML and in 14 of 116 MLL(−) AML patients (P=1.000). K-Ras mutations were detected in 8 of 20 MLL(+) ALL patients compared with 29 of 280 MLL(−) ALL patients (P=0.001). K-Ras mutations were detected in 2 of 16 MLL(+) AML patients compared with 6 of 114 MLL(−) AML patients (P=0.256). Taken together, 10 of 20 MLL(+) ALL children harbored Ras mutations: 4 Gly12Asp, 2 Gly12Val, 1 Gly12Ala and 1 Gly13Asp for K-Ras, and 2 Gly12Asp for N-Ras mutations. The 4 Ras mutations in MLL(+) AML consisted of one each of Gly12Ala and Gln61Pro for N-Ras and one each of Gly12Ala and Gly13Asp for K-Ras mutations. The frequency of Ras mutations was higher in MLL(+) ALL than that in MLL(+) AML, but the difference did not reach statistical significance (P=0.176). Twenty-six of 274 MLL(−) ALL patients harbored N-Ras mutations: 6 Gly12Asp, one each of Gly12Cys and Gly12Ala, 6 Gly13Asp, 5 Gln61Leu, 3 Gln61Lys, 2 Gln61Arg, 1 Gln61His, and one with both Gly12Asp and Gly13Asp. Four of MLL(−) ALL patients had both N-Ras and K-Ras mutations. Fourteen of 116 MLL(−) AML patients harbored N-Ras mutations: 2 Gly12Asp, 2 Gly12Cys, 1 Gly12Ser, 2 Gly13Cys, one each of Gly13Asp and Gly13Arg, 2 Gln61His, 2 Gln61Leu, and 1 Gln61Arg. Six MLL(−) AML patients had K-Ras mutations: 2 Gly12Cys, and one each of Gly12Ala, Gly12Asp, Gly12Ser and Gly13Asp but no mutation at codon 61. One MLL(−) AML patient had both N-Ras and K-Ras mutations. For B-precursor ALL, the frequency of Ras mutations in MLL(+) patients was significantly higher than that of MLL(−) ALL (50% vs. 18.6%, P=0.002). There was no difference in the frequency of Ras mutations between MLL(+) AML and MLL(−) AML (P=0.485). CONCLUSIONS. Ras mutations were detected in 20.7% of children with B-precursor ALL and in 17.7% of childhood AML. MLL(+) B-precursor ALL was highly associated with Ras mutations (50%), especially with K-Ras mutations (40%), while MLL(+) AML was not.

Towards a Purely Oncogenetic Risk Classification of Adult T-ALL: a GRAALL Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 881-881
Author(s):  
Amélie Trinquand ◽  
Aline Tanguy-Schmidt ◽  
Raouf Ben Abdelali ◽  
Jérôme Lambert ◽  
Etienne Lengliné ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Good Prognosis ◽  
Prognostic Impact ◽  
Acute Leukemias ◽  
Ras Mutations ◽  
Genomic Deletions ◽  
High Risk Patients ◽  
Risk Patients

Abstract Abstract 881 T-cell acute lymphoblastic leukemia (T-ALL) represents a heterogeneous group of acute leukemias, which account for 25% of adult ALL. The GRAALL group recently reported a significant improvement in the outcome of BCR-ABL negative adult ALL using an intensified treatment protocol and a significantly better outcome in T-ALL harbouring NOTCH1 and/or FBXW7 (N/F) mutations compared to unmutated cases. Despite this, a third of N/F mutated T-ALL patients relapse and the identification of a T-ALL subgroup with very favorable outcome remains desirable. In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and 2005 trials, we searched for N/K-RAS (exon 1) mutations and PTEN (exon 7 mutations and gene deletion by CGH-array SNP-6 Affymetrix®) defects, which are considered as “type B3” mutations involved in pre-TCR signalling. Overall survival (OS) and event-free survival (EFS) were estimated by the Kaplan-Meier method, and then compared by the log-rank test. NOTCH1 and/or FBXW7 mutations were identified in 143 (67%) of the 212 patients and lack of N/F mutation was associated with a poor prognostic. N-RAS, K-RAS and PTEN mutations were identified in 3/191 (1.6%), 17/191 (8.9%) and 17/175 (9.7%) patients, respectively. PTEN genomic deletions/mutations and N/K-RAS activating mutations were virtually mutually exclusive. N/K-RAS mutations were more frequent in TCR negative phenotype and CNS positive T-ALLs, but did not correlate with other classical parameters, EGIL phenotype, N/F status, or cortico- or chemo-sensitivity. PTEN alterations were more frequent in mature TCR expressing, SIL-TAL+, N/F unmutated cases with high leukemic bulk tumors, but did not significantly differed with respect to age, gender, CNS involvement, cortico- or chemo-sensitivity. When analyzed separately, N/K-RAS mutations or PTEN genomic abnormalities demonstrated trends to a worse outcome. We then analyzed the effect of N/K-RAS mutations and/or PTEN genomic abnormalities on the good prognosis associated with N/F mutations by a multivariate Cox model for EFS and OS, entering the two N/F and RAS/PTEN covariates, as well as an interaction term. The prognostic significance of N/F mutations was still observed (HR, 0.26 [95% CI, 0.15–0.46] and 0.26 [95% CI, 0.14–0.49] with P<0.0001 for EFS and OS, respectively), with a significant interaction between N/F and RAS/PTEN mutations (P=0.03 and 0.05 for EFS and OS, respectively. In other terms, the favorable impact of N/F mutation was still observed in, and was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 out of 189 [51%] patients in the present cohort) and all other patients (49%, including 13% N/F and RAS/PTEN mutated cases) as high-risk patients (Figures 1A and 1B). Comparing this refined oncogenetic classifier to the simple N/F classification, hazard ratios for high-risk patients increased from 2.6 (95% CI, 1.7–4.0) to 3.25 (95% CI, 2.0–5.3) for EFS and from 2.5 (95% CI, 1.5–4.0) to 3.3 (95% CI, 1.9–5.8) for OS. When adjusting the effect of the new N/F-RAS-PTEN classifier to age (using the 35-year cutoff) and WBC (using the 100.109/L cut-off), the oncogenetic classifier remained the only significant prognostic covariate (HR= 3.2 (95% CI, 1.9–5.15) and 3.2 (95% CI, 1.9–5.6); P<0.0001 and <0.0001, for EFS and OS, respectively). The prognostic impact was maintained when GRAALL-2003 and GRAALL-2005 patients were analysed separately. Taken together, these data demonstrate that detection of RAS and PTEN mutations add significant prognostic value to assessment of N/F status, allowing identification of nearly 50% very good prognosis T-ALL adults. Figure 1A Figure 1A. Figure 1B Figure 1B. Disclosures: No relevant conflicts of interest to declare.

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

Abstract 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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