scholarly journals Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia

2008 ◽  
Vol 205 (4) ◽  
pp. 751-758 ◽  
Author(s):  
Elisabetta Flex ◽  
Valentina Petrangeli ◽  
Lorenzo Stella ◽  
Sabina Chiaretti ◽  
Tekla Hornakova ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Gene Expression Signature ◽  
Poor Response ◽  
Response To Therapy ◽  
Janus Kinase ◽  
Leukemic Cells ◽  
Cell Precursor ◽  
Induced Apoptosis

Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. We report that somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis. All mutations were missense, and some were predicted to destabilize interdomain interactions controlling the activity of the kinase. Three mutations that were studied promoted JAK1 gain of function and conferred interleukin (IL)-3–independent growth in Ba/F3 cells and/or IL-9–independent resistance to dexamethasone-induced apoptosis in T cell lymphoma BW5147 cells. Such effects were associated with variably enhanced activation of multiple downstream signaling pathways. Leukemic cells with mutated JAK1 alleles shared a gene expression signature characterized by transcriptional up-regulation of genes positively controlled by JAK signaling. Our findings implicate dysregulated JAK1 function in ALL, particularly of T cell origin, and point to this kinase as a target for the development of novel antileukemic drugs.

ABT-737 Restores Prednisolone Sensitivity In Early T-Cell Precursor Acute Lymphoblastic Leukemia With High MEF2C Expression

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3830-3830
Author(s):  
Sachiko Goto ◽  
Toshihiko Imamura ◽  
Atsushi Fujiki ◽  
Takuya Nakatani ◽  
Yoshifumi Hirashima ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Combination Treatment ◽  
Lymphoblastic Leukemia ◽  
Gene Expression Pattern ◽  
Annexin V ◽  
Poor Response ◽  
High Expression ◽  
Cell Precursor ◽  
Potential Therapeutic Target

Abstract Background Early T-cell precursor-acute lymphoblastic leukemia (ETP-ALL) has been identified as high-risk subtype of pediatric T cell acute lymphoblastic leukemia (T-ALL). ETP-ALL is characterized by lack of expression of CD1a and CD8, weak or absent expression of CD5 and aberrant expression of myeloid and hematopoietic stem cell markers, such as CD13, CD33, CD34 and CD117. Because conventional chemotherapy is not fully effective for this subtype, potential therapeutic target should be explored. Here, we assessed gene expression pattern of the transcriptional factors related to differentiation of lymphoid and myeloid cells in ETP-ALL to determine the potential therapeutic target for this particular subtype. Patients and Methods Thirty-one patients with T-ALL treated in Kyoto Prefectural University of Medicine and affiliated hospitals were classified in ETP-ALL or non- ETP ALL based on the results of surface marker analysis by FACS. To compare the gene expression pattern of transcriptional factors related to differentiation of myeloid and lymphoid cells in ETP-ALL with those in non-ETP-ALL, real time RT-PCR (RQ-PCR) was performed to determine expression level of C/EBPa, ID2, NOTCH1, LYL1, IL7R, LMO2, MEF2C, PU.1, and FLT3 in primary leukemic cells from twenty-one patients with T-ALL (ETP-ALL: 9, non ETP-ALL: 12) based on the availability of appropriate RNA. To assess the relationship between high MEF2C expression and prednisolone (PSL) /Bcl2 inhibitor (ABT-737) sensitivity, cell proliferation of Jurkat (not expressing MEF2C) and Loucy (expressing MEF2C) cells cultured with serial concentration of PSL and/or ABT-737 was measured with the WST-1 assay to determine the 50% growth inhibitory concentration (IC50) of these agents. BaF3 cells expressing MEF2C (BaF3-MEF2C) was also generated using retrovirus gene transduction system (MSCV) and cultured with serial concentration of PSL/ABT-737 to determine the IC50 of PSL/ABT-737. Apoptosis was determined by Annexin V/PI staining. Viability of primary leukemic blasts of ETP-ALL and non-ETP-ALL, which were co-cultured with murine stromal cell(MS-5 cell) and treated with PSL and/or ABT-737, was also determined by Annexin V/PI staining. Results Thirty-one patients diagnosed with T-ALL were classified in ETP-ALL (N=10) or non- ETP ALL (N=21). Although 5 patients in ETP-ALL experienced induction failure (IF), none of the patients in non-ETP-ALL experienced IF (p<0.05). The 5-year EFS in ETP-ALL was significantly inferior than that in non-ETP-ALL ( 40±15.5% vs 76.1±9.2%, log-rank p<0.05). However, the 5-year OS was not significantly different in two groups (67±15.7% in ETP-ALL vs 81±8.5% in non-ETP ALL). RQ-PCR analysis determined that MEF2C and FLT3 was expressed more in ETP-ALL than in non-ETP ALL (MEF2C: p=0.039, FLT3: p=0.014). Because MEF2C augments Bcl2 activity to inhibit the apoptosis, we explored whether high expression of MEF2C was associated with PSL poor response and Bcl2 inhibitor restored the sensitivity to PSL. Combination treatment of PSL and ABT-737 resulted in the significant reduction of IC50 of PSL in Loucy cell (combination index, CI: 0.39). In addition, apoptotic cells increased when Loucy cells were treated with PSL (25mM) in combination with ABT-737 (10nM) compared to be treated with PSL (25mM) alone. In contrast, combination treatment did not reduce significantly IC50 of PSL in Jurkat cell (CI: 1.12). The combination treatment of PSL and ABT-737 also resulted in the significant reduction of IC50 of PSL in BaF3-MEF2C compared to BaF3 cells. Finally, treatment of ABT-737(10nM) in combination with PSL (50 or 200 mM) reduced viability of primary leukemic blasts of ETP-ALL with high expression of MEF2C more profoundly than the treatment of PSL (50 or 200 mM) alone. Conclusions These findings suggest that high expression of MEF2C is associated with PSL poor response and Bcl2 inhibitor restores PSL sensitivity in ETP-ALL in vitro. Thus, Bcl2 inhibitor might be therapeutic option for ETP-ALL with high expression of MEF2C. Disclosures: No relevant conflicts of interest to declare.

Characterization of immunoglobulin and T-cell receptor gene patterns in B-cell precursor acute lymphoblastic leukemia of childhood.

1990 ◽  
Vol 8 (3) ◽  
pp. 431-442 ◽  
Author(s):  
C A Felix ◽  
D G Poplack ◽  
G H Reaman ◽  
S M Steinberg ◽  
D E Cole ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Receptor Gene ◽  
Cell Receptor ◽  
Leukemic Cells ◽  
Cell Precursor

Immunoglobulin (Ig) and T-cell receptor (TCR) genes were examined in the lymphoblasts of 70 children with immunophenotypically defined B-cell precursor acute lymphoblastic leukemia (ALL). The most frequent genes to rearrange were Ig heavy (H) chain (93%) and TCR delta (79%), followed by TCR gamma (49%), Ig kappa and/or lambda light (L) chain (46%), TCR alpha (46%), and TCR beta (29%). Thus, despite their putative "B-cell precursor" lineage, these leukemias manifest a remarkably high incidence of TCR gene rearrangements. While certain patterns predominate, there is considerable heterogeneity in Ig and TCR genotypes in this disease. No significant associations were found between Ig and TCR genotype and commonly used prognostic factors including age, sex, race, WBC, French-American-British (FAB) subtype, or cytogenetics. However, the lymphoblasts of three of six patients who failed to achieve initial remission had germline patterns of every Ig and TCR gene, a genotype not observed in the leukemic cells from any of the 64 patients who achieved complete remission (p2 = .0007). This study suggests that particular Ig and TCR genotypes may be of clinical relevance in childhood B-cell precursor ALL. The finding of rearranged TCR genes in a large proportion of cases raises fundamental questions about early lineage commitment and lymphocyte differentiation along B-cell and T-cell pathways.

scholarly journals Absence of Biallelic TCRγ Deletion Predicts Early Treatment Failure in Pediatric T-Cell Acute Lymphoblastic Leukemia

2010 ◽  
Vol 28 (24) ◽  
pp. 3816-3823 ◽  
Author(s):  
Alejandro Gutierrez ◽  
Suzanne E. Dahlberg ◽  
Donna S. Neuberg ◽  
Jianhua Zhang ◽  
Ruta Grebliunaite ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Induction Chemotherapy ◽  
Lymphoblastic Leukemia ◽  
Poor Response ◽  
Leukemic Cells ◽  
Comparative Genomic ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Induction Failure ◽  
Dna Pcr

Purpose To identify children with T-cell acute lymphoblastic leukemia (T-ALL) at high risk of induction chemotherapy failure by using DNA copy number analysis of leukemic cells collected at diagnosis. Patients and Methods Array comparative genomic hybridization (CGH) was performed on genomic DNA extracted from diagnostic lymphoblasts from 47 children with T-ALL treated on Children's Oncology Group Study P9404 or Dana-Farber Cancer Institute Protocol 00-01. These samples represented nine patients who did not achieve an initial complete remission, 13 who relapsed, and 25 who became long-term, event-free survivors. The findings were confirmed in an independent cohort of patients by quantitative DNA polymerase chain reaction (DNA-PCR), an assay that is well suited for clinical application. Results Analysis of the CGH findings in patients in whom induction chemotherapy failed compared with those in whom induction chemotherapy was successful identified the absence of biallelic TCRγ locus deletion (ABD), a characteristic of early thymocyte precursors before V(D)J recombination, as the most robust predictor of induction failure (P < .001). This feature was also associated with markedly inferior event-free (P = .002) and overall survival (P < .001) rates: 25% versus 58% and 25% versus 72%, respectively. Using a rapid and inexpensive quantitative DNA-PCR assay, we validated ABD as a predictor of a poor response to induction chemotherapy in an independent series of patients. Conclusion Lymphoblasts from children with T-ALL should be evaluated at diagnosis for deletion within the TCRγ locus. Patients lacking biallelic deletion, which confers a high probability of induction failure with contemporary therapy, should be assigned to alternative therapy in the context of a prospective clinical trial.

scholarly journals Inhibition of BCL11B induces downregulation of PTK7 and results in growth retardation and apoptosis in T-cell acute lymphoblastic leukemia

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Kehan Li ◽  
Cunte Chen ◽  
Rili Gao ◽  
Xibao Yu ◽  
Youxue Huang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Growth Retardation ◽  
Lymphoblastic Leukemia ◽  
Downstream Target ◽  
B Cell Leukemia ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Induced Apoptosis ◽  
Necrosis Factor ◽  
Aggressive Subtype

AbstractT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of leukemia with poor prognosis, and biomarkers and novel therapeutic targets are urgently needed for this disease. Our previous studies have found that inhibition of the B-cell leukemia/lymphoma 11B (BCL11B) gene could significantly promote the apoptosis and growth retardation of T-ALL cells, but the molecular mechanism underlying this effect remains unclear. This study intends to investigate genes downstream of BCL11B and further explore its function in T-ALL cells. We found that PTK7 was a potential downstream target of BCL11B in T-ALL. Compared with the healthy individuals (HIs), PTK7 was overexpressed in T-ALL cells, and BCL11B expression was positively correlated with PTK7 expression. Importantly, BCL11B knockdown reduced PTK7 expression in T-ALL cells. Similar to the effects of BCL11B silencing, downregulation of PTK7 inhibited cell proliferation and induced apoptosis in Molt-4 cells via up-regulating the expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and p27. Altogether, our studies suggest that PTK7 is a potential downstream target of BCL11B, and downregulation of PTK7 expression via inhibition of the BCL11B pathway induces growth retardation and apoptosis in T-ALL cells.

scholarly journals DNA Methylation in T-Cell Acute Lymphoblastic Leukemia: In Search for Clinical and Biological Meaning

2021 ◽  
Vol 22 (3) ◽  
pp. 1388
Author(s):  
Natalia Maćkowska ◽  
Monika Drobna-Śledzińska ◽  
Michał Witt ◽  
Małgorzata Dawidowska
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Epigenetic Modification ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Global Methylation ◽  
Current State ◽  
History Of ◽  
Cell Acute Lymphoblastic Leukemia

Distinct DNA methylation signatures, related to different prognosis, have been observed across many cancers, including T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological neoplasm. By global methylation analysis, two major phenotypes might be observed in T-ALL: hypermethylation related to better outcome and hypomethylation, which is a candidate marker of poor prognosis. Moreover, DNA methylation holds more than a clinical meaning. It reflects the replicative history of leukemic cells and most likely different mechanisms underlying leukemia development in these T-ALL subtypes. The elucidation of the mechanisms and aberrations specific to (epi-)genomic subtypes might pave the way towards predictive diagnostics and precision medicine in T-ALL. We present the current state of knowledge on the role of DNA methylation in T-ALL. We describe the involvement of DNA methylation in normal hematopoiesis and T-cell development, focusing on epigenetic aberrations contributing to this leukemia. We further review the research investigating distinct methylation phenotypes in T-ALL, related to different outcomes, pointing to the most recent research aimed to unravel the biological mechanisms behind differential methylation. We highlight how technological advancements facilitated broadening the perspective of the investigation into DNA methylation and how this has changed our understanding of the roles of this epigenetic modification in T-ALL.

Dysregulation of miR‐125b predicts poor response to therapy in pediatric acute lymphoblastic leukemia

2018 ◽  
Vol 120 (5) ◽  
pp. 7428-7438 ◽  
Author(s):  
Nashwa El‐Khazragy ◽  
Amal Ali Elshimy ◽  
Safaa Shawky Hassan ◽  
Safa Matbouly ◽  
Gehan Safwat ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Poor Response ◽  
Response To Therapy ◽  
Pediatric Acute Lymphoblastic Leukemia

scholarly journals Low molecular weight B cell growth factor induces proliferation of human B cell precursor acute lymphoblastic leukemias

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 132-138 ◽  
Author(s):  
B Wormann ◽  
SR Mehta ◽  
AL Maizel ◽  
TW LeBien
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Growth Factor ◽  
Cell Growth ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Cell Precursor ◽  
B Cell Growth Factor ◽  
B Cell Precursors

Experiments were conducted to determine the effect of low mol wt B cell growth factor (L-BCGF) on B cell precursor acute lymphoblastic leukemia (ALL). L-BCGF induced a significant increase in 3H-TdR incorporation in 28 of 37 bone marrow aspirates from patients with B cell precursor ALL, with stimulation indices ranging from 2 to 129. Fluorescence-activated cell sorting confirmed that in five of seven patients the common acute lymphoblastic leukemia antigen (CALLA)/CD10 positive leukemic cells were responding directly to L-BCGF. L-BCGF was capable of inducing, in some patients, an increase in absolute viable cells and could also induce colony formation in vitro. The response of B cell precursor ALL was not attributable to beta IL 1, IL 2, or gamma interferon. These results indicate that the majority of B cell precursor ALL undergo a proliferative response to L-BCGF, suggesting a regulatory role for this lymphokine in the growth of B cell precursors.

scholarly journals Early T-Cell Precursor Leukemia Has a Higher Risk of Induction-Related Infection among T-Cell Acute Lymphoblastic Leukemia in Adult

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Kangyu Huang ◽  
Min Dai ◽  
Qiuli Li ◽  
Nannan Liu ◽  
Dainan Lin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Induction Chemotherapy ◽  
Mixed Infection ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Chemotherapy Response ◽  
Cell Precursor ◽  
Resistant Infection ◽  
Risk Predictors

Background. Infections are an important cause of morbidity and mortality for acute lymphoblastic leukemia (ALL). However, the reports regarding risk factors of induction-related infection are roughly unknown/limited in adult T-ALL during induction chemotherapy. Methods. We performed a retrospective cohort study for the prevalence and risk predictors of induction-related infection among consecutive T-ALL patients ( N = 97 ) enrolled in a PDT-ALL-LBL clinical trial. Of 97 patients with T-ALL enrolled in the trial, 46 were early T-cell precursor (ETP) ALL and 51 were non-ETP ALL. Results. When compared with non-ETP, ETP ALL subtype was characterized with lower neutrophil count ( 1.35 × 10 9 /L vs. 8.7 × 10 9 /L, P < 0.001 ) and lower myeloid percentage in the bone marrow (13.35% vs. 35.31%, P = 0.007 ). Additionally, ETP ALL had longer neutropenia before diagnosis ( P < 0.001 ), as well as during induction chemotherapy ( P < 0.001 ). Notably, the ETP cohort experienced higher cumulative incidence of clinically documented infections (CDI; 33.33%, P = 0.001 ), microbiologically documented infections (MDI; 45.24%, P = 0.006 ), resistant infection (11.9%, P = 0.013 ), and mixed infection (21.43%, P = 0.003 ), respectively, than those of the non-ETP cohort. Furthermore, multivariable analysis revealed that T-ALL mixed infection was more likely related to chemotherapy response (OR, 0.025; 95% CI 0.127-0.64; P = 0.012 ) and identified myeloid percentage as a predictor associated with ETP-ALL mixed infection (OR, 0.915; 95% CI 0.843-0.993; P = 0.033 ), with ROC-defined cut-off value of 2.24% in ETP cohorts. Conclusions. Our data for the first time demonstrated that ETP-ALL characterized with impaired myelopoiesis were more susceptible to induction-related infection among T-ALL populations.

Sign in / Sign up

Export Citation Format

Share Document