Activating FLT3 mutations in CD117/KIT+ T-cell acute lymphoblastic leukemias

Blood ◽  
2004 ◽  
Vol 104 (2) ◽  
pp. 558-560 ◽  
Author(s):  
Elisabeth Paietta ◽  
Adolfo A. Ferrando ◽  
Donna Neuberg ◽  
John M. Bennett ◽  
Janis Racevskis ◽  
...  
Keyword(s):  
T Cell ◽  
Receptor Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Genetic Aberrations ◽  
Constitutive Activation ◽  
Activating Mutations ◽  
Flt3 Mutations ◽  
Acute Myeloid

Abstract Activating FLT3 mutations are the most common genetic aberrations in acute myeloid leukemia (AML), resulting in the constitutive activation of this receptor tyrosine kinase (RTK), but such mutations are rarely found in acute lymphoblastic leukemia (ALL). Here we describe a unique subset of de novo adult T-cell ALL (T-ALL) cases that coexpress CD117/KIT and cytoplasmic CD3 (CD117/KIT+ ALL). Activating mutations in the FLT3 RTK gene were found in each of 3 CD117/KIT+ cases that were analyzed, but not in 52 other adult T-ALL samples from the same series that lacked CD117/KIT expression. Our results indicate the need for clinical trials to test the efficacy of drugs that inhibit the FLT3 RTK in this subset of patients with T-ALL. (Blood. 2004;104:558-560)

scholarly journals HRX involvement in de novo and secondary leukemias with diverse chromosome 11q23 abnormalities [see comments]

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3197-3203 ◽  
Author(s):  
SP Hunger ◽  
DC Tkachuk ◽  
MD Amylon ◽  
MP Link ◽  
AJ Carroll ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Myelogenous Leukemia ◽  
Chromosome Band ◽  
11Q23 Abnormalities ◽  
Acute Myeloid ◽  
Secondary Leukemias

Abstract Chromosome band 11q23 is a site of recurrent translocations and interstitial deletions in human leukemias. Recent studies have shown that the 11q23 gene HRX is fused to heterologous genes from chromosomes 4 or 19 after t(4;11)(q21;q23) and t(11;19)(q23;p13) translocations to create fusion genes encoding proteins with structural features of chimeric transcription factors. In this report, we show structural alterations of HRX by conventional Southern blot analyses in 26 of 27 de novo leukemias with cytogenetically diverse 11q23 abnormalities. The sole case that lacked HRX rearrangements was a t(11;17)-acute myeloid leukemia with French-American-British M3-like morphology. We also analyzed 10 secondary leukemias that arose after therapy with topoisomerase II inhibitors and found HRX rearrangements in 7 of 7 with 11q23 translocations, and in 2 of 2 with unsuccessful karyotypes. In total, we observed HRX rearrangements in 35 leukemias involving at least nine distinct donor loci (1q32, 4q21, 6q27, 7p15, 9p21–24, 15q15, 16p13, and two 19p13 sites). All breakpoints localized to an 8-kb region that encompassed exons 5–11 of HRX, suggesting that fusion proteins containing similar portions of HRX may be consistently created in leukemias with 11q23 abnormalities. We conclude that alteration of HRX is a recurrent pathogenetic event in leukemias with 11q23 aberrations involving many potential partners in a variety of settings including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia in blast crisis, and topoisomerase II inhibitor- induced secondary leukemias of both the myeloid and lymphoid lineages.

scholarly journals Acute myeloid leukemia chimeric antigen receptor T-cell immunotherapy: how far up the road have we traveled?

2018 ◽  
Vol 9 (6) ◽  
pp. 135-148 ◽  
Author(s):  
Sarah K Tasian
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Antigen Receptor ◽  
Successful Implementation ◽  
Car T Cell ◽  
Car T ◽  
Acute Myeloid

Chemotherapy resistance and relapse remain significant sources of mortality for children and adults with acute myeloid leukemia (AML). Further intensification of conventional cytotoxic chemotherapy is likely not feasible due to the severity of acute and long-term side effects upon normal tissues commonly induced by these drugs. Successful development and implementation of new precision medicine treatment approaches for patients with AML, which may improve leukemia remission and diminish toxicity, is thus a major priority. Tumor antigen-redirected chimeric antigen receptor (CAR) T-cell immunotherapies have induced remarkable responses in patients with relapsed or chemorefractory B-lymphoblastic leukemia, and similar strategies are now under early clinical study in adults with relapsed/refractory AML. However, potential on target/off tumor toxicity of AML CAR T-cell immunotherapies, notably aplasia of normal myeloid cells, may limit broader implementation of such approaches. Careful selection of optimal target antigens, consideration of toxicity mitigation strategies, and development of methodologies to circumvent potential CAR T-cell resistance are essential for successful implementation of cellular immunotherapies for patients with high-risk AML.

scholarly journals Characterization of flow cytometric immuno-phenotyping of acute myeloid leukemia with minimal differentiation and acute T-cell lymphoblastic leukemia: A retrospective cross-sectional study

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1170
Author(s):  
Enass Abdul Kareem Dagher Al-Saadi ◽  
Marwa Ali Abdulnabi ◽  
Faris Hanoon Jaafar
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Antigen Expression ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Cross Sectional ◽  
Acute Myeloid

Background: Acute leukemias (ALs) are a heterogeneous group of malignancies with various clinical, morphological, immunophenotypic, and molecular characteristics. Distinguishing between lymphoid and myeloid leukemia is often performed by flow cytometry. This study aimed to evaluate the immunophenotypic characterization and expression of immuno-markers in both acute myeloid leukemia (AML-M0) and acute T-cell lymphoblastic leukemia (T-ALL). Methods: A retrospective cross-sectional study was conducted in the Pathology Department/Teaching Laboratories/Medical City/Iraq and included all patients newly diagnosed with AL from 5 January to 10 December 2018. Immunophenotypic analysis was performed on bone marrow samples, freshly collected in EDTA tubes. Flow cytometry (Canto-2 BD) was used, with laser excitation of blue and red wavelengths. A panel of monoclonal antibodies (MoAbs) was used for diagnosis, using a SSC/CD45 gating strategy. Results: The study showed 41.6% of AML-M0 patients had no aberrant antigen expression, while 33.3%, 16.6%,  8.3%, and 8.3% had aberrant CD7, CD56, CD2, and CD19, respectively. In 16.6% of AML-M0 cases more than one aberrant antigen was expressed. With regard to T-ALL, 7.0% were pro-T type, 58.0% were pre-T, 13.0% were cortical, and 22.0% were mature-T type. In 55.5% of patients with T-ALL there was no aberrant antigen expression. Conclusion: We concluded that most patients with AML-M0 have no aberrant antigen expression. In patients with T-ALL, the pre-T type is most common, according to the European Group for the Immunological Classification of Leukemias (EGIL) classification. Patients with T-ALL also generally lack aberrant antigen expression.

scholarly journals NPM1 and FLT3-ITD/TKD Gene Mutations in Acute Myeloid Leukemia

2021 ◽  
Author(s):  
Shano Naseem ◽  
Jogeshwar Binota ◽  
Neelam Varma ◽  
Harpreet Virk ◽  
Subhash Varma ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Gene Mutations ◽  
Total Leucocyte Count ◽  
Molecular Testing ◽  
Therapeutic Implications ◽  
Number Of Patients ◽  
Flt3 Mutations ◽  
Acute Myeloid

Background: A number of mutations have been reported to occur in patients with acute myeloid leukemia (AML), of which NPM1 and FLT3 genes mutations are the commonest and have important diagnostic and therapeutic implications. Material and Methods: Molecular testing for NPM1 and FLT3 genes was performed in 92 de-novo AML patients. The frequency and characteristics of NPM1 and FLT3 mutations were analyzed. Results: Nucleophosmin 1(NPM1) and FMS-like tyrosine kinase 3 (FLT3) mutations were seen in 22.8% and 16.3% of patients, respectively. Amongst FLT3 mutations, FLT3-ITD mutation was seen in 8.7% cases, FLT3- TKD in 5.4%, and FLT3-ITD+TKD in 2.2% cases. Certain associations between the gene mutations and clinical characteristics were found, including in NPM1 mutated group- female preponderance, higher incidence in M4/M5 categories and decreased expression of CD34 and HLA-DR; and in FLT3-ITD mutated group- higher age of presentation, higher total leucocyte count and blast percentage. Conclusion- AML patients with NPM1 and FLT3 mutations have differences in clinical and hematological features, which might represent their different molecular mechanism in leukemogenesis. The frequency of NPM1 and FLT3 mutations in this study was comparable to reports from Asian countries but lower than that reported from western countries. However, as the number of patients in the study was less, a larger number of patients need to be studied to corroborate these findings.

scholarly journals Transformation of the acute myeloid leukemia to acute B cell lymphoblastic leukemia with CAR-T cell therapy: a case report and review of the literature

2021 ◽  
Author(s):  
Yanan Zhang ◽  
Fengan Liu ◽  
Xue Wang ◽  
Jiang Cao ◽  
Wei Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Lymphoid Leukemia ◽  
T Cell Therapy ◽  
Car T Cell Therapy ◽  
Car T ◽  
Acute Myeloid

Lineage conversion is used to describe acute myeloid or lymphoid leukemia becomes the opposite at relapse.We report a 4-year-old child with acute myeloid leukemia who was converted to acute lymphoblastic leukemia at relapse and received chimeric antigen receptor T (cell) therapy for reference.

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