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.

Correlation of karyotype and immunophenotype in childhood acute lymphoblastic leukemia.

1988 ◽  
Vol 6 (1) ◽  
pp. 56-61 ◽  
Author(s):  
C H Pui ◽  
D L Williams ◽  
P K Roberson ◽  
S C Raimondi ◽  
F G Behm ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Chromosomal Change ◽  
Cytogenetic Feature

To correlate leukemic cell karyotype with immunophenotype, we studied 364 children with acute lymphoblastic leukemia (ALL). A prognostically favorable cytogenetic feature, hyperdiploidy greater than 50 chromosomes, was found in 33% of cases classified as common ALL antigen positive (CALLA+) early pre-B (common) ALL, in contrast to 18% of pre-B cases (P = .012), 5% of T cell cases (P less than .001), and none of the B cell cases (P less than .001) or cases of CALLA negative (CALLA-) early pre-B ALL (P = .002). The frequency of translocations, an adverse cytogenetic feature, was significantly lower in CALLA+ early pre-B ALL cases (35%) than in B cell (100%; P less than .0001), pre-B (59%; P less than .001), or CALLA- early pre-B (62%; P = .016) cases. Thus, patterns of chromosomal change differ widely among the major immunophenotypic groups of ALL and may account for reported differences in responsiveness to treatment.

scholarly journals Advances of target therapy on NOTCH1 signaling pathway in T-cell acute lymphoblastic leukemia

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Ruyue Zheng ◽  
Menglin Li ◽  
Shujuan Wang ◽  
Yanfang Liu
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Signaling Pathway ◽  
Target Therapy ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Gene Mutations ◽  
Hematopoietic Stem ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Signaling Pathway

AbstractT-cell acute lymphoblastic leukemia (T-ALL) is one of the hematological malignancies. With the applications of chemotherapy regimens and allogeneic hematopoietic stem cell transplantation, the cure rate of T-ALL has been significantly improved. However, patients with relapsed and refractory T-ALL still lack effective treatment options. Gene mutations play an important role in T-ALL. The NOTCH1 gene mutation is the important one among these genetic mutations. Since the mutation of NOTCH1 gene is considered as a driving oncogene in T-ALL, targeting the NOTCH1 signaling patheway may be an effective option to overcome relapsed and refractory T-ALL. This review mainly summarizes the recent research advances of targeting on NOTCH1 signaling pathway in T-ALL.

Simulataneous Vaccination and Delayed Lymphocyte Infusion for Enhancement of Immune Reactivity Against Acute Lymphoblastic Leukemia or Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5248-5248
Author(s):  
Craig A. Mullen ◽  
Olga Sevastianova
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
T Cell Responses ◽  
Myelogenous Leukemia ◽  
Lymphoid Tissues ◽  
Spleen Cells ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Cell Responses

Abstract BACKGROUND: Delayed lymphocyte infusion (DLI) can be employed as an antileukemia immune therapy when patients with leukemia relapse after allogeneic hematopoietic stem cell transplantation (HSCT). While effective in patients with chronic myelogenous leukemia, it is generally ineffective with relapse of acute lymphoblastic leukemia (ALL). This ineffectiveness may be multifactorial and possible reasons include rapid leukemia cell growth in ALL, reduced propensity to apoptosis signals, and poor presentation of antigens present on lymphoblasts resulting in failure to generate a significant immune response. If the failure of malignant lymphoblasts in marrow and lymphoid tissues to elicit meaningful T cell responses plays a role in the ineffectiveness of DLI, it is possible that therapeutic vaccines may be able to ameliorate this barrier. We have recently demonstrated that vaccination immediately prior to HSCT enhances antigen specific T cell responses in the post-transplant immune repertoire (Bone Marrow Transplantation, 35:793–801, 2005.) HYPOTHESIS: Vaccination with leukemia related antigens at the time of DLI will increase donor T cell responses to leukemia related antigens without exacerbation of GVHD responses to ubiquitous host minor histocompatibility antigens (mHA). METHODS: We employ a murine MHC matched allogeneic HSCT model in which 6 antigens are molecularly characterized. C3.SW mice are donors and C57BL/6 mice are recipients. In this model the H7 mHA is the immunodominant antigen, while alloresponses to H3 and H13 are also present. By using spontaneously arising lymphoblastic leukemia/lymphoma cells from Ig-cmyc transgenic male C57BL/6 as the model malignancy in a female to female transplant the male HY associated antigens Uty, Dby and Smcy can be used as antigens restricted to the lymphoid malignancy. Four weeks after allogeneic HSCT mice were vaccinated with 107 cells expressing the HY antigens and the C57BL/6 H7, H3 and H13 minor antigens. The cells used for pre-DLI vaccination were either irradiated male C57BL/6 spleen cells or irradiated male malignant lymphoblasts. One day later mice received iv infusion of 107 spleen cells from C3.SW female donor mice previously primed against HY antigens by immunization with male C3.SW cells. Ten days interferon gamma Elispot assays were performed on HSCT recipient spleen cells using the peptide-defined antigens. RESULTS: Vaccination of HSCT recipients with male spleen cells 1 day prior to DLI from HY immune donors significantly increased T cell responses to HY peptide epitopes. Recipients of DLI alone harbored 40 interferon secreting cells per 106, while combination of vaccination and DLI yielded 94 per 106(p < 0.05). In contrast, there was no change in the number of T cells responding to the H7, H3 and H13 mHA. DLI only exhibited 26 per 106 while DLI plus vaccine exhibited 27 per 106 (p < 0.05). Whole cell irradiated lymphoblasts were not as effective as irradiated splenocytes in augmenting the HY responses, although they were equally effective in producing T cell responses in normal, nontransplanted mice. CONCLUSIONS: Simultaneous vaccination and DLI can lead to significant expansion of donor cells potentially reactive with antigens present on malignant lymphoblasts without exacerbation of T cell responses to ubiquitous mHA associated with GVHD. Current work is exploring methods by which indirect presentation of antigens from lymphoblasts can be enhanced, since it is unlikely that vaccines relying on direct antigen presentation by lymphoblasts will be effective.

Frequency of NUP214-ABL1 Oncogene in Patients with T-Cell Acute Lymphoblastic Leukemia (T-ALL) and Analysis of the Activity of Imatinib and Nilotinib in NUP214-ABL1-Expressing T-ALL Cell Lines.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 710-710
Author(s):  
Alfonso Quintas-Cardama ◽  
Weigang Tong ◽  
Taghi Manshouri ◽  
Jan Cools ◽  
D. Gary Gilliland ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Lines ◽  
Inhibitory Activity ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcript ◽  
Lymphoblastic Lymphoma ◽  
Abl Kinase ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Kinase Inhibitory Activity

Abstract The fusion of ABL1 with BCR results in the hybrid BCR-ABL1 oncogene that encodes the constitutively active Bcr-Abl tyrosine kinase encountered in the majority of patients with chronic myeloid leukemia (CML) and in approximately 30% of pts with B-cell acute lymphoblastic leukemia (B-ALL). Recently, the episomal amplification of ABL1 has been described in 6% of pts with T-ALL (Nat Genet2004;36:1084–9). Molecular analysis demonstrated the oncogenic fusion of ABL1 with the nuclear pore complex protein NUP214 (NUP214-ABL1). We screened 29 pts with T-cell lymphoblastic lymphoma (T-LBL) and T-ALL for the presence of the NUP214-ABL1 fusion transcript by RT-PCR using specific primers for the 5 different transcripts thus far described. Three (10%) pts were found to express this fusion transcript, including 2 with T lymphoblastic lymphoma (NUP214 exon 31) and 1 with T-ALL (NUP214 exon 29). This was confirmed by direct sequencing in all cases. All pts received therapy with hyperCVAD and achieved a complete remission (CR). However, 2 of them died 6 and 9 months into therapy, respectively. One other pt remains in CR (19+ months) by morphologic and flow cytometry criteria. However, NUP214-ABL1 is still detectable in peripheral blood by nested PCR, thus suggesting minimal residual disease (MRD). We then studied the activity of the tyrosine kinase inhibitors imatinib and nilotinib in the NUP214-ABL1-expressing cell lines PEER and BE-13. Although PEER and BE-13 cell viability was reduced with both agents, the IC50 was almost 10-fold higher for imatinib (643 nM) than for nilotinib (68 nM) (F test, p<0.001), which parallels the 10− to 30− fold higher Abl kinase inhibitory activity of nilotinib compared to imatinib in BCR-ABL-expressing cells. Nilotinib also potently inhibited the cell proliferation of BE-13 cells (IC50 131 nM). In contrast, Jurkat cells, a T-ALL cell line which does not carry NUP214-ABL1, were remarkably resistant to both imatinib and nilotinib with an IC50 values greater than 5 μM indicating that the cytotoxicity mediated by both TKIs is not related to a general toxic effect on T-ALL cell lines. The inhibition of cellular proliferation by imatinib and nilotinib was associated with a dose- and time-dependent induction of apoptosis in both PEER and BE-13 cells. In Western blotting, higher inhibition of phospho-Abl and phospho-CRKL (a surrogate of Bcr-Abl kinase status) was observed in PEER cells upon exposure to nilotinib as compared with imatinib at their respective IC50 concentrations for cell growth inhibition. We conclude that NUP214-ABL1 can be detected in 10% of pts with T-cell malignancies and its detection can be used as a sensitive marker of MRD. Imatinib and nilotinib potently inhibits the growth of NUP214-ABL1-expressing cells. Given the higher Abl kinase inhibitory activity of nilotinib with respect to imatinib, this agent must be further investigated in clinical studies targeting patients with T-ALL and T-LBL expressing the NUP214-ABL1 fusion kinase.

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.

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 (> 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.

Phase II Trial of the Anti-CD19 Bispecific T Cell–Engager Blinatumomab Shows Hematologic and Molecular Remissions in Patients With Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia

2014 ◽  
Vol 32 (36) ◽  
pp. 4134-4140 ◽  
Author(s):  
Max S. Topp ◽  
Nicola Gökbuget ◽  
Gerhard Zugmaier ◽  
Petra Klappers ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clinical Activity ◽  
Hematopoietic Stem ◽  
Dismal Prognosis ◽  
Bispecific T Cell Engager

Purpose Patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis. CD19 is homogenously expressed in B-precursor ALL and can be targeted by the investigational bispecific T cell–engager antibody blinatumomab. A phase II trial was performed to determine clinical activity in this patient cohort. Patients and Methods Thirty-six patients with relapsed or refractory B-precursor ALL were treated with blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval in a single-arm study with a dose-finding stage and an extension stage. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Major secondary end points included minimal residual disease (MRD) response, rate of allogeneic hematopoietic stem-cell transplantation (HSCT) realization, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs). Results Median age was 32 years (range, 18 to 77 years). Twenty-five patients (69%) achieved a CR or CRh, with 88% of the responders achieving an MRD response. Median OS was 9.8 months (95% CI, 8.5 to 14.9), and median RFS was 7.6 months (95% CI, 4.5 to 9.5). Thirteen responders (52%) underwent HSCT after achieving a CR or CRh. The most frequent AE during treatment was pyrexia (grade 1 or 2, 75%; grade 3, 6%). In six patients with nervous system or psychiatric disorder AEs and in two patients with cytokine release syndrome, treatment had to be interrupted or discontinued. These medical events were resolved clinically. Conclusion The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.

scholarly journals Abnormalities of the long arm of chromosome 6 in childhood acute lymphoblastic leukemia

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1626-1630 ◽  
Author(s):  
Y Hayashi ◽  
SC Raimondi ◽  
AT Look ◽  
FG Behm ◽  
GR Kitchingman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Suppressor Gene ◽  
Chromosome 6 ◽  
Free Survival ◽  
Structural Abnormalities ◽  
Multistep Process ◽  
Or Genes

To determine the biologic significance of the structural rearrangements of the long arm of chromosome 6(6q) in acute lymphoblastic leukemia (ALL) at diagnosis, we studied 412 consecutive children whose leukemic cell chromosomes had been completely banded and identified 45 (11%) children with this abnormality. The 45 cases were divided into del(6q) only (n = 11), del(6q) and numerical abnormalities (n = 4), del(6q) and structural abnormalities (n = 23), and 6q translocations (n = 7). The breakpoints of del(6q) were subgrouped: del(6)(q15q21) in 11 cases, del(6) (q13q21) in six, del(6)(q21q23) in four, del(6)(q15) in four, del(6)(q15q23) in three, and other deletions in 10 cases. Notably, all these deletions encompassed the 6q21 band, suggesting that this might be the locus of a recessive tumor suppressor gene, the absence of which contributes to malignant transformation or proliferation. Among the seven children with 6q translocations, a previously unidentified nonrandom translocation, t(6;12)(q21;p13) was noted in two cases with an early pre-B immunophenotype. Clinical features and event-free survival were similar among children with or without 6q abnormalities. Overall, children with 6q abnormalities were less likely than those without the abnormality to have a pre-B immunophenotype (P = .03). T- cell immunophenotypes were equally represented in cases with or without 6q abnormalities. However, all four children with del(6q) and a 12p abnormality had early pre-B ALL and all three children with del(6q) and a 9p abnormality had a T-cell immunophenotype. The lack of specificity for a particular immunophenotype may imply that the gene or genes affected by 6q abnormalities are broadly active in the multistep process of lymphoid leukemogenesis. The relatively high frequency of microscopically visible del(6q) indicates the need for molecular studies to identify cases with submicroscopic deletions.

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