Genetic and Clinical Characterization of 45 Acute Leukemia Patients with MLL Gene Rearrangements From a Single Institution.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2477-2477
Author(s):  
Nuno Cerveira ◽  
Susana Lisboa ◽  
Cecília Correia ◽  
Susana Bizarro ◽  
Joana Santos ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Consecutive Series ◽  
Gene Rearrangements ◽  
Fusion Partner ◽  
Older Children ◽  
Single Institution ◽  
Mll Gene

Abstract Abstract 2477 Background: MLL gene rearrangements are found in more than 70% of the cases of infant leukemia, both acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML), but are less frequent in leukemia from older children. MLL translocations are also found in approximately 10% of adult AML and in a small proportion of patients with therapy-related leukemia. Independently of their association with other high-risk features at presentation, MLL rearrangements are in most cases predictive of poor clinical outcome. In this study, we report the clinical characterization and frequency and type of MLL rearrangements present in a consecutive series of 45 patients that were diagnosed with acute leukemia in the Portuguese Oncology Institute, Porto, Portugal, over the last 13 years (1998–2011). Patients and Methods: Conventional cytogenetic, fluorescence in situ hybridization (FISH), and molecular genetic studies (RT-PCR and LDI-PCR) were used to characterize the type and frequency of MLL rearrangements in a consecutive series of 45 Portuguese patients with MLL-related leukemia treated in a single institution between 1998 and 2011. Additionally, a detailed patient clinical characterization was also performed and statistical analysis using the Kaplan-Meier method as used to evaluate patient survival. Results: In 43 patients (96% of the cases) we could identify the fusion partner, the most common being the MLLT3, AFF1, MLLT1, MLLT10, ELL, and MLLT4 genes, accounting for 88% of all cases. In the group of patients with acute lymphoblastic leukemia and an identified MLL fusion partner, 47% showed the presence of an MLL-AFF1 fusion, as a result of a t(4;11). In the remaining cases, a MLL-MLLT3 (27%), a MLL-MLLT1 (20%), or MLL-MLLT4 (7%) rearrangement was found. The most frequent rearrangement found in patients with acute myeloblastic leukemia was the MLL-MLLT3 fusion (42%), followed by MLL-MLLT10 (23%), MLL-MLLT1 (8%), MLL-ELL (8%), MLL-MLLT4 (4%), and MLL-MLLT11 (4%). In three patients, fusions involving MLL and a septin family gene (SEPT2, SEPT6, and SEPT9), were identified. The most frequently identified chromosomal rearrangements were reciprocal translocations, but insertions and deletions, some cryptic, were also observed. In our series, patients with MLL rearrangements were shown to have a poor prognosis, regardless of leukemia subtype and treatment protocol. However, patients that received a bone marrow transplant had a better survival than patients that received chemotherapy alone. Interestingly, children with 1 year or less showed a statistically significant better overall survival when compared with both older children and adults. Conclusions: The use of a combined strategy in the initial genetic evaluation of acute leukemia patients allowed us to characterize the pattern of MLL rearrangements in our institution, including our previous discovery of two novel MLL fusion partners, the SEPT2 and CT45A2 genes, and a very rare MLL-MLLT4 fusion variant. Disclosures: No relevant conflicts of interest to declare.

Immunophenotypic Investigation of Infant Acute Lymphoblastic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2547-2547 ◽  
Author(s):  
Alexander Popov ◽  
Grigory Tsaur ◽  
Tatiana Verzhbitskaya ◽  
Olga Streneva ◽  
Egor Shorikov ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Age Groups ◽  
Older Age ◽  
Study Group ◽  
Gene Rearrangements ◽  
Age Group ◽  
Older Children ◽  
Cell Precursor ◽  
Mll Gene

Abstract Abstract 2547 Acute lymphoblastic leukemia (ALL) in children less than 1 year old is the relatively rare disease with specific biological features and poor outcome. It is also characterized by high incidence of MLL gene rearrangements. Immunophenotype of infants' leukemia varies due to presence or absence of MLL-rearrangements. Aim of the study. description of immunophenotype in infant acute lymphoblastic leukemia. Methods. Totally 421 cases of pediatric acute leukemia (AL) were studied. 81 patients (39 boys and 42 girls) aged from 5 days to 11 months were included in the study group. Their data was compared to 332 cases of acute leukemia in older children. Tumor cells immunophenotyping was performed by 6–8-color flow cytometry. Detection of various types of MLL-gene rearrangements was done by simultaneous application of chromosomal banding analysis, fluorescence in-situ hybridization, reverse-transcriptase polymerase chain reaction (PCR) and long-distance inverse PCR. Results. There were 54 (66.7%) ALL cases in the study group. ALL was found less frequently in infants than in older children (66.7% and 88.5% respectively, p<0.0001) while percentage of acute myeloid leukemia cases was higher in infants (27.2% and 10.0% respectively, p=0.0001). EGIL immunophenotypes distribution also differed between infants and older children. BI-ALL was the most common immunological ALL type in infant ALL (55.6% vs 3.3% in older age group, p<0.0001), while BII-ALL was notably less frequent compared with other age groups (33.3% and 77.1% respectively, p<0.0001). T-lineage ALL was also less frequent in infants (3.7% vs 14.3% in older age group) although difference did not achieve statistical significance (p=0.0536). Totally infant ALL were mainly presented by B-cell precursor ALL (BCP-ALL) – 51 patients (94.4%). Various types of MLL-rearrangements were found in 40 (74.1%) patients (pts) out of 54 infants ALL cases. Among them 21 pts (52.5%) carried MLL-AF4 fusion gene, 8 pts (20.0%) – MLL-MLLT1, 5 pts (12.5%) – MLL-MLLT3, 3 pts (7.5%) – MLL-EPS15, 1 pt (2.5%) – MLL-MLLT10, 1 pt (2.5%) – MLL-AFF3 and 1 pt (2.5%) had MLL-rearrangement with unidentified partner gene. Significant immunophenotypic differences were observed in patients with and without MLL gene rearrangements. Number of cases in those tumor cells expressed CD10, CD20, CD45, CD133, CD15, NG2 significantly varied between MLL-positive and MLL-negative groups (p=0.0001, p<0.0001, p=0.0008, p=0.0018, p=0.0306 and p<0.0001 correspondingly). NG2-positivity represented the highest overall correct prediction (OCP) rate for presence of MLL-rearrangements (95.5%). Diagnostic accuracy of CD20-negativity and CD45-positivity was slightly lower (87.5% and 86.3% respectively) while OCP for CD10-negativity (78.4%), CD133-positivity (75.0%) and CD15-positivity (66.7%) was not sufficient enough. Nevertheless CD10-positive BCP-ALL with MLL-rearrangements differed from CD10(+) cases in MLL-germline group. CD10 homogeneous expression was noted in 10 out of 11 MLL-germline patients and in 1 of 10 MLL-rearranged cases (p=0.0011). Although there were found no significant differences in CD22-positive patients' number, CD22(+)-cells percentage was significantly lower in MLL-positive cases (median 89.9%, range 25.2–99.7% and median 99.9%, range 96.0–99.9% respectively, p=0.0026). Thus CD20-negativity, CD10-negativity/low expression, high CD45, CD15, CD65 and NG2 expression, decreased CD22-expression are immunophenotypic signatures of MLL-rearranged infant ALL, although NG2 has the highest diagnostic efficacy. Interestingly there were no markers able to distinguish MLL-AF4-positive cases from patients carrying other types of MLL-rearrangements. Even NG2 expression intensity did not differ between these groups (p=0.2720). Except BCP-ALL pts, two cases of T-lineage ALL and one mature B-ALL (without other Burkitt lymphoma features) were found. Conclusion. Thus immunophenotype of ALL in children less than 1 year old differs significantly from patients of older age groups. Infants' B-cell precursor ALL immunophenotype varies greatly due to the presence of MLL gene rearrangements. Complex diagnostic immunophenotyping of infants' ALL allows predicting presence of MLL rearrangements and NG2 is the most applicable single marker. Disclosures: No relevant conflicts of interest to declare.

Childhood Acute Lymphoblastic Leukemia With the MLL-ENL Fusion and t(11;19)(q23;p13.3) Translocation

1999 ◽  
Vol 17 (1) ◽  
pp. 191-191 ◽  
Author(s):  
Jeffrey E. Rubnitz ◽  
Bruce M. Camitta ◽  
Hazem Mahmoud ◽  
Susana C. Raimondi ◽  
Andrew J. Carroll ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Fusion Transcript ◽  
Cell Phenotype ◽  
Molecular Characteristics ◽  
Older Children ◽  
Hematopoietic Stem ◽  
Mll Gene

PURPOSE: To determine the molecular characteristics, clinical features, and treatment outcomes of children with acute lymphoblastic leukemia (ALL) and the t(11;19)(q23;p13.3) translocation. PATIENTS AND METHODS: A retrospective analysis of leukemic cell karyotypes obtained from patients with new diagnoses of ALL who were treated at St. Jude Children's Research Hospital or by the Pediatric Oncology Group was performed to identify cases with the t(11;19)(q23;p13.3) translocation. Molecular analyses were performed on these cases to determine the status of the MLL gene and the presence of the MLL-ENL fusion transcript. RESULTS: Among 3,578 patients with ALL and successful cytogenetic analysis, we identified 35 patients with the t(11;19)(q23;p13.3) translocation: 13 infants and 11 older children had B-precursor leukemia, whereas 11 patients had a T-cell phenotype. Although all of the cases examined had MLL rearrangements and MLL-ENL fusion transcripts, outcome varied according to age and immunophenotype. Among B-precursor cases, only two of the 13 infants remain in complete remission, compared with six of the 11 older children. Most strikingly, no relapses have occurred among B-precursor patients 1 to 9 years of age or among T-cell patients. CONCLUSION: Although MLL gene rearrangements are generally associated with a dismal outcome in ALL, two distinct subsets with MLL-ENL fusions have an excellent prognosis. Our results suggest that patients with this genetic abnormality who have T-cell ALL or are 1 to 9 years of age should not be considered candidates for hematopoietic stem-cell transplantation during their first remission.

MLL genomic DNA Breakpoints In Infant Acute Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1350-1350
Author(s):  
Grigory Tsaur ◽  
Claus Meyer ◽  
Alexander Popov ◽  
Olga Plekhanova ◽  
Anatoly Kustanovich ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Genomic Dna ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Chromosome 11 ◽  
Long Distance ◽  
Mll Gene ◽  
Stable Pattern ◽  
Breakpoint Location

Abstract Background Infant acute leukemia is characterized by high incidence of MLL gene rearrangements. Purpose To evaluate the distribution of MLL genomic DNA breakpoints and their relation to several diagnostic parameters among infant acute leukemia. Methods 72 infants with MLL-rearranged acute lymphoblastic leukemia (ALL) (n=52), acute myeloid leukemia (AML) (n=19) and mixed phenotype acute leukemia (n=1) were included in this study based on the availability of DNA material at diagnosis. In the observed group there were 28 boys (39%) and 44 girls (61%) with median age of 4.9 mo (range 0.03-11.9). Genomic DNA breakpoint detection in MLL gene and translocation partner genes (TPG) was performed by long-distance inverse PCR (LDI-PCR). Exon-intron numbering of MLL gene was done according to I. Nilson et al, 1996. Results Majority of ALL cases (n=28; 54%) was characterized by presence of MLL-AF4 fusion gene (FG), less frequently MLL-MLLT1 (n=12; 23%), MLL-MLLT3 (n=7; 13%) and others were found (Table 1). The most common breakpoint location within MLL gene in ALL patients was intron 11, detected in 25 cases (48%). The highest variability of MLL breakpoints was found in MLL-AF4-positive patients: only 11 of 28 (39%) had breakpoints in intron 11. The most stable pattern of MLL genomic DNA breakpoints was observed in MLL-MLLT1-positive patients: 8 of 12 (67%) had breakpoints in intron 11. In AML patients two the most prevalent FGs were MLL-MLLT3 (n=7, 37%) and MLL-MLLT10 (n=5, 26%). The remaining ones are listed in Table 1. The most frequent breakpoints location was intron 8 (8 out of 19, 42%). The most stable pattern was revealed for MLL-MLLT10 FG: MLL breakpoints in 4 of 5 (80%) cases were found in intron 9 (Table 1). ALL patients who had breakpoints in intron 11 were significantly younger (median 3.0 mo, range 0.03-11.6) than all others (median 5.6 mo, range 0.7-11.9) (p=0.025) and than patients with MLL breakpoints in intron 9 (median 6.6 mo, range 3.1-11.9) (p=0.017). For AML cases we did not find any relation between age and breakpoints locations. Distribution of MLL DNA breakpoints was similar in boys and girls and did not depend on type of TPG. Genetic recombinations involving MLL gene predominantly resulted in reciprocal chromosomal translocations (n=62; 86%). Beside them, 6 (11%) insertions were identified in all MLL-MLLT10-positive cases and MLL-SEPT6-positive one. In 11 (15%) patients we found breakpoints within the regions located from 0.7 Kb to 25.4 Kb 3' of the first exon of TPGs (MLLT1 n=9; EPS15 n=1; MYO1F n=1), however fusion transcripts at cDNA level were identified and sequenced in all these cases, indicating a spliced fusion mechanism. 3-way translocations were found in 5 patients and in 1 case we found combination of insertion with interstitial deletion of chromosome 11. The list of reciprocal genes involved in these 6 cases was as follows: CEP164, DNAH6, DCPA1, MCL1 as well as non-coding regions of 2q21.2 and 2p21. We also analyzed breakpoints in TPGs. Except above mentioned spliced fusion cases, the remaining 3 breakpoints in MLLT1 as well as 3 of 4 breakpoints in EPS15 and all breakpoints in MLLT11 were within intron 1 of corresponding genes. In AF4 the major breakpoint region included intron 3 (n=19), intron 4 (n=6) and intron 5 (n=2). We also revealed 2 rare breakpoints in intron 6 and 10. In MLLT3 the most frequent breakpoint location was intron 5 (n=12), additionally 2 cases in intron 5 were identified. In MLLT10 two separate breakpoint locations were found: intron 3 (n=1) and intron 8 (n=3) in combination with intron 9 (n=1). We estimated prognostic significance of MLL breakpoint locations in 31 cases of infant ALL treated by MLL-Baby protocol. 3-year cumulative incidence of relapse was remarkably higher in patients with breakpoints in intron 11 (n=18) in comparison to patients with breakpoint localized from intron 7 to exon 11, inclusively (n=13) (0.85±0.01 and 0.57±0.02, respectively), although difference between these two groups did not achieve statistical significance (p=0.261). Median follow-up time in the observed group was 30 months (range 6–42). Conclusion In the current study we estimated clinical and prognostic significance of MLL and TPG genomic DNA breakpoints in infant acute leukemia. Our data provide additional information of molecular genetic features of MLL-rearranged infant acute leukemia. Disclosures: No relevant conflicts of interest to declare.

FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 812-820 ◽  
Author(s):  
Patrick Brown ◽  
Mark Levis ◽  
Sheila Shurtleff ◽  
Dario Campana ◽  
James Downing ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Gene Rearrangements ◽  
Childhood All ◽  
Activating Mutations ◽  
Mll Gene ◽  
Flt3 Inhibitor ◽  
Targeted Agent

AbstractFMS-like tyrosine kinase 3 (FLT3) is almost universally expressed in B-precursor childhood acute lymphoblastic leukemia (ALL). Cases of ALL with MLL gene rearrangements and those with high hyperdiploidy (&gt; 50 chromosomes) express the highest levels of FLT3, and activating mutations of FLT3 occur in 18% of MLL-rearranged and 28% of hyperdiploid ALL cases. We determined the antileukemic activity of CEP-701, a potent and selective FLT3 inhibitor, in 8 ALL cell lines and 39 bone marrow samples obtained at diagnosis from infants and children with various subtypes of ALL. CEP-701 induced pronounced apoptotic responses in a higher percentage of samples that expressed high levels of FLT3 (74%, n = 23) compared with samples with low levels of expression (8%, n = 13; P = .0003). Sensitivity to FLT3 inhibition was particularly high in samples with MLL gene rearrangements (82%, n = 11; P = .0005), high hyperdiploidy (100%, n = 5; P = .0007), and/or FLT3 mutations (100%, n = 4; P = .0021). Seven of 7 sensitive samples examined by immunoblotting demonstrated constitutively phosphorylated FLT3 that was potently inhibited by CEP-701, whereas 0 of 6 resistant samples expressed constitutively phosphorylated FLT3. We conclude that the FLT3 inhibitor CEP-701 effectively suppresses FLT3-driven leukemic cell survival. Clinical testing of CEP-701 as a novel molecularly targeted agent for the treatment of childhood ALL is warranted.

What Is New? An Update of the MLL Recombinome Including the Three Novel Partner Genes ABI2, PDS5A, and TOP3A

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1351-1351
Author(s):  
Claus Meyer ◽  
Mariana Emerenciano ◽  
Eva A Coenen ◽  
Eric Delabesse ◽  
Charles Herbaux ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Molecular Level ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Patient Specific ◽  
Fusion Partner ◽  
Fusion Transcripts ◽  
Mll Gene ◽  
Diagnostic Center ◽  
Partner Gene

Abstract Abstract 1351 Chromosomal rearrangements of the MLL gene are associated with pediatric and adult de novo as well as therapy related acute myeloid leukemias, acute lymphoid leukemias, biphenotypic leukemias, and myelodysplastic syndromes. So far more than 70 MLL fusion partner genes have been characterized at the molecular level involving nearly all chromosomes. Though 11q23 rearrangements are associated with high-risk leukemias the clinical outcome of MLL rearrangements depends highly on the specific fusion partner involved. Nearly 40% of these partner genes have been identified at the Diagnostic Center of Acute Leukemia (DCAL) including the novel partner genes ABI2, PDS5A and TOP3A by analyzing more than 1400 MLL rearrangements. These rearrangements from 27 different countries include 52 different partner genes. This overview indicates all the specific introns of the translocation partner genes (TPGs) found to be involved in MLL translocations, their chromosomal locations and the type of genetic abnormality that is leading to the MLL fusion. More than 20% of all MLL rearrangements are complex ones. Within these complex rearrangements, the 5' part of the MLL gene is generally fused in frame to one of the most frequent partner genes. But the 3' part of the MLL gene is fused in many cases to a novel so-called “reciprocal MLL partner gene” like DENND4A or LRRTM4. To date more than 90 reciprocal MLL partner genes have been identified. In addition we present a recently analysed 4-way translocation where all four breakpoints could be identified by systematic breakpoint analysis using LDI-PCR. Also three novel “spliced MLL fusions”, a mechanism to generate functional chimeric fusion transcripts, involving MLLT4 (AF6), MYO1F, and CT45A2 have been identified at the DCAL. With these results, the number of genes involved in „spliced MLL fusions“ has increased from eight to eleven. Moreover we present the current breakpoint cluster region (bcr) for the 14 most frequent partner genes, namely AFF1 (AF4), MLLT3 (AF9), MLLT1 (ENL), MLLT10 (AF10), MLLT4 (AF6), ELL, EPS15, MLLT6 (AF17), SEPT6 (AF17), MLLT11 (AF1Q), SEPT9, AFF3 (LAF4), TET1, SEPT5 (PNUTL) and partial tandem duplications. For six patients, no partner gene could be identified at the molecular level and for 5 patients the identified fusion is out of frame. Unfortunetely all attemps to identify functional chimeric fusion transcripts by RACE and RT-PCR failed. These unusual MLL rearrangements probably represent a subclass of MLL abnormalities which have per se no or only a weak ability to transform hematopoeitic cells and are indentified only in the context of other hematopoeitic malignancies like the recently described MLL partner SACM1L. Finally, the determined patient-specific fusion sequences are succesfully used worldwide for minimal residual disease (MRD) monitoring to improve the treatment and outcome of acute leukemia patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Analysis of the Role of Hematopoietic Stem-Cell Transplantation in Infants With Acute Lymphoblastic Leukemia in First Remission and MLL Gene Rearrangements: A Report From the Children's Oncology Group

2011 ◽  
Vol 29 (2) ◽  
pp. 214-222 ◽  
Author(s):  
ZoAnn E. Dreyer ◽  
Patricia A. Dinndorf ◽  
Bruce Camitta ◽  
Harland Sather ◽  
Mei K. La ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Gene Rearrangements ◽  
Oncology Group ◽  
Hematopoietic Stem ◽  
Mll Gene

Purpose Although the majority of children with acute lymphoblastic leukemia (ALL) are cured with current therapy, the event-free survival (EFS) of infants with ALL, particularly those with mixed lineage leukemia (MLL) gene rearrangements, is only 30% to 40%. Relapse has been the major source of treatment failure for these patients. The parallel Children's Cancer Group (CCG) 1953 and Pediatric Oncology Group (POG) 9407 studies were designed to test the hypothesis that more intensive therapy, including dose intensification of chemotherapy, and hematopoietic stem-cell transplantation (HSCT) would improve the outcome for this group of patients. Patients and Methods One hundred eighty-nine infants (CCG 1953, n = 115; POG 9407, n = 74) were enrolled between October 1996 and August 2000. For infants with the MLL gene rearrangement and an appropriate donor, HSCT was the preferred treatment on CCG 1953 and investigator option on POG 9407 after completion of the second phase of therapy. Fifty-three infants underwent HSCT. Results The 5-year EFS rate was 48.8% (95% CI, 33.9% to 63.7%) in patients who received HSCT and 48.7% (95% CI, 33.8% to 63.6%) in patients treated with chemotherapy alone (P = .60). Transplantation outcomes were not affected by the preparatory regimen or donor source. Conclusion Our data suggest that routine use of HSCT for infants with MLL-rearranged ALL is not indicated. However, limited by small numbers, this study should not be considered the definitive answer to this question.

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