scholarly journals RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia

Blood ◽  
2017 ◽  
Vol 130 (15) ◽  
pp. 1722-1733 ◽  
Author(s):  
AHyun Choi ◽  
Anuradha Illendula ◽  
John A. Pulikkan ◽  
Justine E. Roderick ◽  
Jessica Tesell ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Cells ◽  
Enhancer Activity ◽  
Key Points ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Normal Human

Key Points RUNX1 maintains Myb and Myc enhancer activity and is required for leukemogenesis in vivo. RUNX1 inhibition impairs the growth of primary T-ALL patient cells without an effect on normal human hematopoietic cells.

scholarly journals Deletion of Pten in CD45-expressing cells leads to development of T-cell lymphoblastic lymphoma but not myeloid malignancies

Blood ◽  
2016 ◽  
Vol 127 (15) ◽  
pp. 1907-1911 ◽  
Author(s):  
Cristina Mirantes ◽  
Maria Alba Dosil ◽  
David Hills ◽  
Jian Yang ◽  
Núria Eritja ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mouse Model ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Cells ◽  
Hematologic Malignancies ◽  
Lymphoblastic Lymphoma ◽  
Key Points ◽  
Pten Deletion ◽  
Cell Acute Lymphoblastic Leukemia

Key Points CD45-driven expression of Cre generates the first mouse model that allows specific and exclusive deletion of Pten in hematopoietic cells. Pten deletion in CD45-expressing cells causes T-cell acute lymphoblastic leukemia, but no other hematologic malignancies.

scholarly journals The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia

Blood ◽  
2015 ◽  
Vol 125 (1) ◽  
pp. 13-21 ◽  
Author(s):  
Joni Van der Meulen ◽  
Viraj Sanghvi ◽  
Konstantinos Mavrakis ◽  
Kaat Durinck ◽  
Fang Fang ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Lymphoblastic Leukemia ◽  
Specific Tumor ◽  
Key Points ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Gender Specific

Key Points The H3K27me3 demethylase UTX is recurrently mutated in male T-ALL and escapes X-inactivation in female T-ALL blasts and normal T cells. The loss of Utx contributes to T-ALL formation in vivo and UTX inactivation confers sensitivity to H3K27me3 inhibition.

scholarly journals Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia

Blood ◽  
2017 ◽  
Vol 130 (25) ◽  
pp. 2750-2761 ◽  
Author(s):  
Valentina Serafin ◽  
Giorgia Capuzzo ◽  
Gloria Milani ◽  
Sonia Anna Minuzzo ◽  
Marica Pinazza ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Glucocorticoid Resistance ◽  
Glucocorticoid Treatment ◽  
Key Points ◽  
Cell Acute Lymphoblastic Leukemia

Key Points Resistance to glucocorticoid treatment in pediatric T-ALL can be reversed by LCK inhibitors in vitro and in vivo. IL-4 overexpression contributes to LCK-induced glucocorticoid resistance.

PTEN microdeletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events

Blood ◽  
2014 ◽  
Vol 124 (4) ◽  
pp. 567-578 ◽  
Author(s):  
Rui D. Mendes ◽  
Leonor M. Sarmento ◽  
Kirsten Canté-Barrett ◽  
Linda Zuurbier ◽  
Jessica G. C. A. M. Buijs-Gladdines ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Human T Cell ◽  
Key Points ◽  
Inactivation Mechanism ◽  
Cell Acute Lymphoblastic Leukemia

Key Points Microdeletions represent an additional inactivation mechanism for PTEN in human T-cell acute lymphoblastic leukemia. PTEN microdeletions are RAG-mediated aberrations.

scholarly journals V(D)J-mediated Translocations in Lymphoid Neoplasms: A Functional Assessment of Genomic Instability by Cryptic Sites⋆

2002 ◽  
Vol 195 (1) ◽  
pp. 85-98 ◽  
Author(s):  
Rodrig Marculescu ◽  
Trang Le ◽  
Paul Simon ◽  
Ulrich Jaeger ◽  
Bertrand Nadel
Keyword(s):  
T Cell ◽  
Genomic Instability ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Lymphoid Malignancies ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Normal Human ◽  
Hodgkin's Lymphomas ◽  
The Impact

Most lymphoid malignancies are initiated by specific chromosomal translocations between immunoglobulin (Ig)/T cell receptor (TCR) gene segments and cellular proto-oncogenes. In many cases, illegitimate V(D)J recombination has been proposed to be involved in the translocation process, but this has never been functionally established. Using extra-chromosomal recombination assays, we determined the ability of several proto-oncogenes to target V(D)J recombination, and assessed the impact of their recombinogenic potential on translocation rates in vivo. Our data support the involvement of 2 distinct mechanisms: translocations involving LMO2, TAL2, and TAL1 in T cell acute lymphoblastic leukemia (T-ALL), are compatible with illegitimate V(D)J recombination between a TCR locus and a proto-oncogene locus bearing a fortuitous but functional recombination site (type 1); in contrast, translocations involving BCL1 and BCL2 in B cell non-Hodgkin’s lymphomas (B-NHL), are compatible with a process in which only the IgH locus breaks are mediated by V(D)J recombination (type 2). Most importantly, we show that the t(11;14)(p13;q32) translocation involving LMO2 is present at strikingly high frequency in normal human thymus, and that the recombinogenic potential conferred by the LMO2 cryptic site is directly predictive of the in vivo level of translocation at that locus. These findings provide new insights into the regulation forces acting upon genomic instability in B and T cell tumorigenesis.

scholarly journals Homeobox protein TLX3 activates miR-125b expression to promote T-cell acute lymphoblastic leukemia

2017 ◽  
Vol 1 (12) ◽  
pp. 733-747 ◽  
Author(s):  
Laurent Renou ◽  
Pierre-Yves Boelle ◽  
Caroline Deswarte ◽  
Salvatore Spicuglia ◽  
Aissa Benyoucef ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Host Gene ◽  
Key Points ◽  
Homeobox Protein ◽  
Cell Acute Lymphoblastic Leukemia

Key Points TLX3 transactivates LINC00478, the host gene of oncogenic miR-125b-2 in T-ALL. TLX3 and miR-125b contribute to the differentiation arrest and the expansion of transformed T cells.

scholarly journals miR-22-3p Negatively Affects Tumor Progression in T-Cell Acute Lymphoblastic Leukemia

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1726
Author(s):  
Valentina Saccomani ◽  
Angela Grassi ◽  
Erich Piovan ◽  
Deborah Bongiovanni ◽  
Ludovica Di Martino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Target Genes ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Signaling Pathway

T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive disease arising from T-cell precursors. NOTCH1 plays an important role both in T-cell development and leukemia progression, and more than 60% of human T-ALLs harbor mutations in components of the NOTCH1 signaling pathway, leading to deregulated cell growth and contributing to cell transformation. Besides multiple NOTCH1 target genes, microRNAs have also been shown to regulate T-ALL initiation and progression. Using an established mouse model of T-ALL induced by NOTCH1 activation, we identified several microRNAs downstream of NOTCH1 activation. In particular, we found that NOTCH1 inhibition can induce miR-22-3p in NOTCH1-dependent tumors and that this regulation is also conserved in human samples. Importantly, miR-22-3p overexpression in T-ALL cells can inhibit colony formation in vitro and leukemia progression in vivo. In addition, miR-22-3p was found to be downregulated in T-ALL specimens, both T-ALL cell lines and primary samples, relative to immature T-cells. Our results suggest that miR-22-3p is a functionally relevant microRNA in T-ALL whose modulation can be exploited for therapeutic purposes to inhibit T-ALL progression.

scholarly journals Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia

Blood ◽  
2019 ◽  
Vol 133 (21) ◽  
pp. 2291-2304 ◽  
Author(s):  
Diego Sánchez-Martínez ◽  
Matteo L. Baroni ◽  
Francisco Gutierrez-Agüera ◽  
Heleia Roca-Ho ◽  
Oscar Blanch-Lombarte ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Antileukemic Activity ◽  
Car T Cells ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34+ progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient–derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral antigens. Our data support the therapeutic and safe use of fratricide-resistant CD1a-CARTs for relapsed/refractory coT-ALL.

scholarly journals Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia

2017 ◽  
Vol 1 (20) ◽  
pp. 1760-1772 ◽  
Author(s):  
Xavier Cahu ◽  
Julien Calvo ◽  
Sandrine Poglio ◽  
Nais Prade ◽  
Benoit Colsch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Key Points ◽  
Cell Acute Lymphoblastic Leukemia

Key Points BM niches differentially support T-ALL. BM niches differentially protect T-ALL cells from chemotherapy.

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