Frequent deletion in the methylthioadenosine phosphorylase gene in T- cell acute lymphoblastic leukemia: strategies for enzyme-targeted therapy

Methylthioadenosine phosphorylase (MTAP), an enzyme essential for the salvage of adenine and methionine, is deficient in a variety of cancers, including acute lymphoblastic leukemia (ALL). Because the MTAP gene is located adjacent to the tumor-suppressor gene p16 on chromosome 9p21 and more than 60% of T-cell ALL (T-ALL) patients have deletion in the p16 gene, we examined the status of the MTAP gene in T-ALL patients. Quantitative polymerase chain reaction amplification of exon 8 of MTAP showed a deletion in 16 of 48 (33.3%) patients at diagnosis and in 13 of 33 (39.4%) patients at relapse. Southern blot analysis showed that, in addition to deletion of the entire MTAP gene, a common break point was between exons 4 and 5, resulting in deletion of exons 5 through 8. The finding of frequent deficiency of MTAP in T-ALL offers the possibility of an enzyme targeted therapy for T-ALL. MTAP(-) T-ALL-derived cell line, CEM cells were very sensitive to methionine deprivation, with cell viability at 50% of control as early as 48 hours after methionine deprivation. In contrast, methionine deprivation had little effect on the viability of normal lymphocytes or on their proliferative response to phytohemagglutinin. Alanosine, an inhibitor of AMP synthesis, inhibited the growth of both MTAP(+) (Molt-4 and Molt-16) and MTAP(-) (CEM and HSB2) cell lines. However, the addition of methylthioadenosine, the substrate of MTAP, protected the MTAP(+) cells but not the MTAP(-) cells from alanosine toxicity. These findings suggest the possibility of targeting MTAP for selective therapy of T-ALL.

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The Tumor Suppressor Gene hCDC4 Is Frequently Mutated in Human T-Cell Acute Lymphoblastic Leukemia with Functional Consequences for Notch Signaling

Cancer Research ◽

10.1158/0008-5472.can-06-4381 ◽

2007 ◽

Vol 67 (12) ◽

pp. 5611-5616 ◽

Cited By ~ 131

Author(s):

Alena Malyukova ◽

Takeaki Dohda ◽

Natalie von der Lehr ◽

Shahab Akhondi ◽

Martin Corcoran ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Tumor Suppressor ◽

Notch Signaling ◽

Tumor Suppressor Gene ◽

Lymphoblastic Leukemia ◽

Suppressor Gene ◽

Human T Cell ◽

Functional Consequences ◽

Cell Acute Lymphoblastic Leukemia

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Phase 2 study of pembrolizumab for measurable residual disease in adults with acute lymphoblastic leukemia

Blood Advances ◽

10.1182/bloodadvances.2020002403 ◽

2020 ◽

Vol 4 (14) ◽

pp. 3239-3245

Author(s):

Ryan D. Cassaday ◽

Kelsey-Leigh A. Garcia ◽

Jonathan R. Fromm ◽

Mary-Elizabeth M. Percival ◽

Cameron J. Turtle ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Quantitative Polymerase Chain Reaction ◽

Philadelphia Chromosome ◽

Stevens Johnson Syndrome ◽

Phase 2 ◽

Phase 2 Study ◽

Measurable Residual Disease

Abstract The presence of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) confers a poor prognosis. CD19-targeted immunotherapy is effective against MRD but is logistically challenging, potentially toxic, and not applicable to T-cell ALL. We thus hypothesized that inhibition of PD-1 with pembrolizumab could also be effective for MRD, but without lineage restriction. The primary objective of this phase 2 study was to evaluate the efficacy of pembrolizumab in patients with ALL and MRD. Key eligibility criteria included adults with B- or T-cell ALL and MRD detectable by multiparameter flow cytometry or quantitative polymerase chain reaction from bone marrow aspirate (BMA) despite chemotherapy (plus ABL kinase inhibitor if Philadelphia chromosome positive). Pembrolizumab 200 mg IV was given every 3 weeks. Response was assessed by BMA using methods that previously detected MRD. The primary end point was complete MRD response rate. We stopped enrollment early; only 1 of 12 (8%) experienced a complete MRD response, which lasted 3 weeks. Interestingly, this patient had previously received hematopoietic cell transplantation and CD19-targeted chimeric antigen receptor–modified T-cell therapy and was the only patient to experience an immune-related adverse event from pembrolizumab (grade 3 Stevens-Johnson syndrome). Median overall survival from enrollment was 12.7 months. In summary, pembrolizumab had minimal activity against MRD but was generally well tolerated. These data can be compared with ongoing anti-PD-1 combination studies in ALL, and they further establish the role of trials specifically for patients with MRD. This trial was registered at www.clinicaltrials.gov as #NCT02767934.

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Abstract 1945: Degradation of ERG transcription factor as a targeted therapy in B-cell and T-cell acute lymphoblastic leukemia

10.1158/1538-7445.am2018-1945 ◽

2018 ◽

Author(s):

Xiaoju Wang ◽

Caleb Cheng ◽

Yuanyuan Qiao ◽

Lanbo Xiao ◽

Cynthia Wang ◽

...

Keyword(s):

Transcription Factor ◽

Targeted Therapy ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Cell Acute Lymphoblastic Leukemia

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PI3K/AKT/mTORC1 and MEK/ERK signaling in T-cell acute lymphoblastic leukemia: New options for targeted therapy

Advances in Biological Regulation ◽

10.1016/j.advenzreg.2011.09.019 ◽

2012 ◽

Vol 52 (1) ◽

pp. 214-227 ◽

Cited By ~ 14

Author(s):

Alberto M. Martelli ◽

Giovanna Tabellini ◽

Francesca Ricci ◽

Camilla Evangelisti ◽

Francesca Chiarini ◽

...

Keyword(s):

Targeted Therapy ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Lymphoblastic Leukemia ◽

Erk Signaling ◽

Cell Acute Lymphoblastic Leukemia

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

Blood ◽

10.1182/blood.v76.8.1626.bloodjournal7681626 ◽

1990 ◽

Vol 76 (8) ◽

pp. 1626-1630 ◽

Cited By ~ 4

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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Multiple tumor-suppressor gene 1 inactivation is the most frequent genetic alteration in T-cell acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v87.6.2180.bloodjournal8762180 ◽

1996 ◽

Vol 87 (6) ◽

pp. 2180-2186 ◽

Cited By ~ 73

Author(s):

JM Cayuela ◽

A Madani ◽

L Sanhes ◽

MH Stern ◽

F Sigaux

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Lymphoblastic Leukemia ◽

Genetic Defect ◽

Suppressor Gene ◽

Genetic Alteration ◽

Multiple Tumor ◽

Cell Acute Lymphoblastic Leukemia

No constant genetic alteration has yet been unravelled in T-cell acute lymphoblastic leukemia (T-ALL), and, to date, the most frequent alteration, the SIL-TAL1 deletion, is found in approximately 20% of cases. Recently, two genes have been identified, the multiple tumor- suppressor gene 1 (MTS1) and multiple tumor-suppressor gene 2 (MTS2), whose products inhibit cell cycle progression. A characterization of the MTS locus organization allowed to determine the incidence of MTS1 and MTS2 inactivation in T-ALL. MTS1 and MTS2 configurations were determined by Southern blotting using 8 probes in 59 patients with T- ALL (40 children and 19 adults). Biallelic MTS1 inactivation by deletions and/or rearrangements was observed in 45 cases (76%). Monoallelic alterations were found in 6 cases (10%). The second MTS1 allele was studied in the 4 cases with available material. A point mutation was found in 2 cases. The lack of MTS1 mRNA expression was observed by Northern blot analysis in a third case. A normal single- strand conformation polymorphism pattern of MTS1 exons 1alpha and 2 was found and MTS1 RNA was detected in the fourth case, but a rearrangement occurring 5′ to MTS1 exon 1 alpha deleting MTS1 exon 1Beta was documented. One case presented a complex rearrangement. Germline configuration for MTS1 and MTS2 was found in only 7 cases. The localization of the 17 breakpoints occurring in the MTS locus were determined. Ten of them (59%) are clustered in a 6-kb region located 5 kb downstream to the newly identified MTS1 exon 1Beta. No rearrangement disrupting MTS2 was detected and more rearrangements spared MTS2 than MTS1 (P<.01). MTS1 but not MTS2 RNA was detected by Northern blotting in the human thymus. These data strongly suggest that MTS1 is the functional target of rearrangements in T-ALL. MTS1 inactivation, observed in at least 80% of T-ALL, is the most consistent genetic defect found in this disease to date.

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Ku70 is Associated with the Frequency of Chromosome Translocation in Human Lymphocytes After Radiation and T-Cell Acute Lymphoblastic Leukemia

10.21203/rs.3.rs-858112/v1 ◽

2021 ◽

Author(s):

Zhenbo Cheng ◽

Yupeng Wang ◽

Lihuang Guo ◽

Jiancheng Li ◽

Wei Zhang ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Protein Level ◽

Lymphoblastic Leukemia ◽

Quantitative Polymerase Chain Reaction ◽

Human Lymphocytes ◽

Chromosome Translocation ◽

X Rays ◽

Cell Acute Lymphoblastic Leukemia ◽

Chemical Inhibition

Abstract Background: Chromosome translocation is one of the most common chromosomal causes to T-cell acute lymphoblastic leukemia (T-ALL). Ku70 is one of the key factors of error-prone DNA repair that may end in translocation. So far, the direct correlation between Ku70 and translocation has not been assessed. Our study aimed to investigate the association of Ku70 and translocation in human lymphocytes after radiation and T-ALL. Methods: Peripheral blood lymphocytes (PBLs) from volunteers and human lymphocyte cell line AHH-1were irradiated with X-rays to form chromosome translocations. The frequency of translocation was detected by fluorescence in situ hybridization (FISH), meanwhile, the expression of Ku70 was also detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. Furthermore, Ku70 interference, overexpression and chemical inhibition were used in AHH-1 cell lines to confirm the correlation. Finally, we detected the expression of Ku70 in T-ALL samples with or without translocation. Results: Expression of Ku70 and frequencies of translocation were both significantly increased in PBLs after irradiated by X-rays, and a positive correlation between the expression (both mRNA and protein level) of Ku70 and the frequency of translocation was detected (r = 0.4877, P = 0.004; r = 0.3038, P = 0.0358 respectively). Moreover, Ku70 interference decreased the frequency of translocations while the frequency of translocations was not significantly affected after Ku70 overexpression. The expression of Ku70 and frequencies of translocation were both significantly increased in cells after irradiated combined with chemical inhibition (P <0.01). The protein level and mRNA level of Ku70 in T-ALL with translocation were significantly higher than T-ALL with normal karyotype (P = 0.009, P = 0.049 respectively). Conclusions: Ku70 is closely associated with the frequency of chromosome translocation in human lymphocytes after radiation and T-ALL. Ku70 might be a radiation damage biomarker and a potential tumor therapy target.

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