MicroRNAs as Modulators of the Immune Response in T-Cell Acute Lymphoblastic Leukemia

Acute lymphoblastic leukaemia (ALL) is an aggressive haematological tumour driven by the malignant transformation and expansion of B-cell (B-ALL) or T-cell (T-ALL) progenitors. The evolution of T-ALL pathogenesis encompasses different master developmental pathways, including the main role played by Notch in cell fate choices during tissue differentiation. Recently, a growing body of evidence has highlighted epigenetic changes, particularly the altered expression of microRNAs (miRNAs), as a critical molecular mechanism to sustain T-ALL. The immune response is emerging as key factor in the complex multistep process of cancer but the role of miRNAs in anti-leukaemia response remains elusive. In this review we analyse the available literature on miRNAs as tuners of the immune response in T-ALL, focusing on their role in Natural Killer, T, T-regulatory and Myeloid-derived suppressor cells. A better understanding of this molecular crosstalk may provide the basis for the development of potential immunotherapeutic strategies in the leukemia field.

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Down-Regulation of Mir-26b and Its Inhibition on the Growth of T Cell Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v126.23.2440.2440 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2440-2440

Author(s):

Tian Yuan ◽

Yaling Yang ◽

Jeffrey You ◽

Daniel Lin ◽

Kefeng Lin ◽

...

Keyword(s):

Gene Expression ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Cell Growth ◽

Cell Lines ◽

Lymphoblastic Leukemia ◽

Expression Level ◽

Rt Pcr ◽

Altered Expression ◽

Cell Acute Lymphoblastic Leukemia

Abstract Introduction: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy accounting for 15% of pediatric and 25% of adult acute lymphoblastic leukemia (ALL) cases. With current chemotherapies and transplantation therapy, there are still 25-50% T-ALL patients that suffer from relapse and have a poor outcome. MicroRNAs (miRNAs or miRs) are endogenous small non-coding RNAs (containing about 22 nucleotides in length). miRs function at posttranscriptional level as negative regulators of gene expression and exert their regulatory function through binding to target mRNAs and silencing gene expression. To better understand the pathogenesis and develop the new therapeutic targets of T-ALL, we have developed a Pten tumor suppressor knockout T-ALL mouse model and profiled miRs from the mouse Pten deficient T-ALL. miR-26b was one of the miRs that were found down-regulated in the mouse Pten deficient T-ALL. Recent studies showed that the aberrant expression of miR-26b is implicated in several types of cancer. The expression level of miR-26b and its role of in T-ALL, however, are unknown. We investigated if the expression level of miR-26b is aberrant in T-ALL and the effect of potentially altered expression on the growth of human T-ALL cells. Methods: We conducted miR array profiling to identify differentially expressed miRs in the mouse Pten deficient T-ALLs compared with preneoplastic thymocyte controls. We validated expression levels of several miRs, including miR-26b, that are differentially expressed in mouse and human T-ALL cells using quantitative RT-PCR. We also overexpressed miR-26b using a lentivirus based vector in human T-ALL cell lines to assess its effect on cell growth and apoptosis. Results: Employing miR array profiling, we identified a subset of miRs that exhibited marked altered expression in the mouse Pten deficient T-ALL cells. Quantitative RT-PCR validated that the expression level of miR-26b in the mouse Pten deficient T-ALL cells was markedly lower in comparison to that of preneoplastic thymocytes. To determine if miR-26b expression level is also altered in human T-ALL, we performed quantitative RT-PCR on a panel of human T-ALL cell lines. Indeed, the expression level of miR-26b is significantly lower in the human T-ALL cell lines when compared with that of normal thymocytes. To functionally assess if miR-26b plays a role in the cell growth of human T-ALL cells, we expressed exogenous miR-26b in a panel of human T-ALL cell lines. We demonstrated that the expression of exogenous miR-26b significantly reduced the proliferation and promoted apoptosis of several human T-ALL cell lines. Conclusions: Our results demonstrated that miR-26b is down-regulated in T-ALL and the expression of exogenous miR-26b elicits deceased cell proliferation and increased apoptosis of human T-ALL. These results suggest that miR-26b may function as a tumor suppressor in the development of T-ALL and further characterization of the target and regulation of miR-26b may have therapeutic implications. Disclosures No relevant conflicts of interest to declare.

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Role of the T-Cell Acute Lymphoblastic Leukemia Oncoprotein TLX1/HOX11 in Chromatin Dynamics and Gene Regulatory Networks.

Blood ◽

10.1182/blood.v110.11.56.56 ◽

2007 ◽

Vol 110 (11) ◽

pp. 56-56

Author(s):

Irene Riz ◽

Kristin K. Baxter ◽

Hyo Jung Lee ◽

Reza Behnam ◽

Teresa S. Hawley ◽

...

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Dna Binding ◽

Cell Fate ◽

Malignant Transformation ◽

Binding Sites ◽

Lymphoblastic Leukemia ◽

Cell Acute Lymphoblastic Leukemia

Abstract Homeodomain proteins (homeoproteins) have long been recognized as powerful transcriptional regulators. Inappropriate expression of these transcription factors often leads to major developmental malformations or malignant transformation. The in vitro DNA binding sites of homeoproteins are short sequences that are widely distributed throughout the genome and some canonical binding sites have been shown to be functionally important at distances >20 kb away from the nearest transcription start site. In addition to DNA-binding activity, several homeoproteins have been demonstrated to interact with chromatin-modifying enzymes. For example, we and others have reported that the TLX1 homeoprotein of T-cell acute lymphoblastic leukemia (T-ALL) inhibits the PP1/PP2A serine/threonine phosphatases (I. Riz and R.G. Hawley, Oncogene 24: 5561–5575, 2005) and more recently have found that TLX1 modulates histone/transcription factor acetyltransferase CBP activity (I. Riz et al., Oncogene 26: 4115–4123, 2007). PP1/PP2A and CBP are complex molecular machines integrating diverse regulatory pathways that impact on cell survival, proliferation and differentiation outcomes. Organogenesis and malignant transformation - despite obvious differences - share a common requirement for high-order cooperativity of transcription factors and transcriptional cofactors in regulating the expression of multiple sets of genes executing cell fate shifts. Targeting key regulatory nodes in order to coordinately regulate multiple genes is a common strategy of virus induced cell-transformation: accordingly, PP1/PP2A and CBP are targeted by transforming viral proteins. The Groucho/TLE (transducin-like Enhancer-of-split) family of corepressors are another example of master regulators of cell fate; for instance, it was reported that triggering the MAPK signaling cascade inactivates TLE corepressors leading to coordinated derepression of a large number of genes involved in cell proliferation. We now demonstrate that TLX1 interferes with TLE1 repressive function. By streptavidin affinity-based precipitation of biotinylated recombinant TLX1 protein (TLX1 fused to a biotinylation peptide) we show in vivo interaction of TLX1 and TLE1 in several different cell types, including human T-ALL and neuroblastoma cells. Interaction of TLX1 with TLE1 occurs via an Engrailed homology 1 (Eh1)-like domain as documented by GST pull-down assays and laser scanning confocal microscopy. Transient transfection experiments indicate that TLX1 prevents TLE1-mediated repression of reporter genes. Furthermore, in the context of endogenous chromatin structure, TLX1 derepresses the bHLH transcription factor gene, ACSL1(HASH1), a well characterized target of the HES1/TLE1 repressor complex. The process requires direct interaction of TLX1 with TLE1 and binding of TLX1 to DNA, since a point mutation in the Eh1-like motif or deletion of the third helix of the TLX1 homeodomain abrogated the effect. Additional data to be presented suggest a long-range mechanism of transcriptional regulation by TLX1: we propose that “transcriptional activation” by TLX1 (and, by analogy, other homeoproteins that interact with TLE corepressors) results in part from the chaperoned redistribution of TLE corepressors from proximal promoter regions of target genes to distal chromatin regulatory sites.

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GFI1 cooperates with IKAROS/IKZF1 to activate gene expression in T-cell acute lymphoblastic leukemia

10.1101/2021.03.08.434336 ◽

2021 ◽

Author(s):

Wenxiang Sun ◽

Jingtao Guo ◽

David McClellan ◽

Alexandra Poeschla ◽

Diana Bareyan ◽

...

Keyword(s):

T Cell ◽

Transcriptional Control ◽

Protein Complexes ◽

Lymphoblastic Leukemia ◽

Transcriptional Profiling ◽

T Cell Development ◽

Key Factor ◽

Full Complement ◽

Cell Acute Lymphoblastic Leukemia ◽

Activate Gene

AbstractGrowth factor independence-1 (GFI1) is a transcriptional repressor and master regulator of normal and malignant hematopoiesis. Repression by GFI1 is attributable to recruitment of LSD1-containing protein complexes via its SNAG domain. However, the full complement of GFI1 partners in transcriptional control is not known. We show that in T-ALL cells, GFI1 and IKAROS are transcriptional partners that co-occupy regulatory regions of hallmark T cell development genes. Transcriptional profiling reveals a subset of genes directly transactivated through the GFI1—IKAROS partnership. Among these is NOTCH3, a key factor in T-ALL pathogenesis. Surprisingly, NOTCH3 transactivation by GFI1 and IKAROS requires the GFI1 SNAG domain but occurs independent of SNAG—LSD1 binding. GFI1 variants deficient in LSD1 binding fail to transactivate NOTCH3, but conversely, small molecules that disrupt the SNAG—LSD1 interaction while leaving the SNAG primary structure intact stimulate NOTCH3 expression. These results identify a non-canonical transcriptional control mechanism in T-ALL which supports GFI1-mediated transactivation in partnership with IKAROS and suggest competition between LSD1-containing repressive complexes and others favoring transactivation.

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Heterogeneity of T-cell lymphoblastic malignancies

Blood ◽

10.1182/blood.v55.5.806.806 ◽

1980 ◽

Vol 55 (5) ◽

pp. 806-810 ◽

Cited By ~ 43

Author(s):

LM Nadler ◽

EL Reinherz ◽

HJ Weinstein ◽

CJ D'Orsi ◽

SF Schlossman

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Tumor Cells ◽

Human Peripheral Blood ◽

Lymphoblastic Leukemia ◽

Cell Subset ◽

Disease Process ◽

Suppressor Cells ◽

Lymphoblastic Lymphoma ◽

Cell Acute Lymphoblastic Leukemia

Abstract To determine the T-cell lineage of the malignant lymphoblast in lymphoblastic lymphoma, tumor cells from nine patients were phenotyped employing a T-cell subset specific heteroantisera, TH2. The normal human peripheral blood T-cell compartment is composed of 80% TH2- negative and 20% TH2-positive T cells, as defined by reactivity with subset specific heteroantisera. Human suppressor cells are TH2 reactive, whereas helper cells are TH2 unreactive. Tumor cells from the majority of patients with lymphoblastic lymphoma were TH2 reactive in contrast to the lack of reactivity previously described in the majority of patients with T-cell acute lymphoblastic leukemia. Comparative clinical studies, including disease presentation and course, were correlated with the presence of the TH2 antigen on the tumor cell. These results provide evidence to support the notion of heterogeneity in the T-lymphoblastic malignancies and suggest that lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia are probably not a single disease process.

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MicroRNA as a Prognostic and Diagnostic Marker in T-Cell Acute Lymphoblastic Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms22105317 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5317

Author(s):

Katarzyna Gębarowska ◽

Anna Mroczek ◽

Jerzy Kowalczyk ◽

Monika Lejman

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Lymphoblastic Leukemia ◽

Cellular Functions ◽

Altered Expression ◽

Cell Acute Lymphoblastic Leukemia ◽

The Subject ◽

Lower Variability ◽

Next Generation Sequencing Ngs ◽

Cell Proliferations

T cell acute lymphoblastic leukemia (T-ALL) is a biologically and genetically heterogeneous disease with a poor prognosis overall and several subtypes. The neoplastic transformation takes place through the accumulation of numerous genetic and epigenetic abnormalities. There are only a few prognostic factors in comparison to B cell precursor acute lymphoblastic leukemia, which is characterized by a lower variability and more homogeneous course. The microarray and next-generation sequencing (NGS) technologies exploring the coding and non-coding part of the genome allow us to reveal the complexity of the genomic and transcriptomic background of T-ALL. miRNAs are a class of non-coding RNAs that are involved in the regulation of cellular functions: cell proliferations, apoptosis, migrations, and many other processes. No miRNA has become a significant prognostic and diagnostic factor in T-ALL to date; therefore, this topic of investigation is extremely important, and T-ALL is the subject of intensive research among scientists. The altered expression of many genes in T-ALL might also be caused by wide miRNA dysregulation. The following review focuses on summarizing and characterizing the microRNAs of pediatric patients with T-ALL diagnosis and their potential future use as predictive factors.

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Siglec-15 Is a Novel Immunomodulatory Protein and Therapeutic Target in Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2021-153647 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 515-515

Author(s):

Claire E. Pillsbury ◽

Jairo A. Fonseca ◽

Jodi Dougan ◽

Hasan Abukharma ◽

Gloria Gonzalez-Flamenco ◽

...

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

B Cell ◽

Healthy Donor ◽

Lymphoblastic Leukemia ◽

Leukemia Cells ◽

Soluble Form ◽

Cell Acute Lymphoblastic Leukemia

Abstract Immunotherapies have recently shown efficacy in treatment of aggressive, refractory pediatric B cell acute lymphoblastic leukemia (B-ALL), which remains one of the leading causes of cancer-related death in children. The immune evasion mechanisms of B-ALL are still being explored to discover new therapeutic targets and improve patient outcomes. Recent reports have implicated a role for the molecule Siglec-15 (Sig15) in regulating immune response in solid tumor-infiltrating macrophages. Our lab has found higher expression of SIGLEC15 at the RNA level in primary pediatric B-ALL as compared to healthy donor controls, as well as at the RNA and protein levels across a panel of B-ALL, T cell acute lymphoblastic leukemia (T-ALL), and diffuse large B cell lymphoma (DLBCL) cell lines compared to healthy donor PBMCs. Higher expression of SIGLEC15 in pediatric B-ALL samples from the TARGET database correlates with markers of PKC and NFκB activation known to drive B-ALL leukemogenesis, which we have demonstrated to regulate Sig15 RNA and protein expression in vitro. Knockout of Siglec15 expression in a BCR-ABL1 + murine model of B-ALL engrafted in immunocompetent and Rag1 -/- immunodeficient recipients resulted in leukemia clearance in immunocompetent, but not immunodeficient, recipients and 100% survival (Figure A, p=0.01 Sig15 KO into WT vs. Rag1 -/-). Further study indicates that Siglec15 expression on these leukemia cells suppresses T cell effector and memory population expansion at 7 days post-engraftment (Figure B) and correlates with higher levels of IL-10 and lower levels of CCL17 present in the bone marrow, representing a more immunosuppressive bone marrow milieu. These data suggest a prominent role for Sig15 in the suppression of adaptive immune response to B-ALL as well as other hematological malignancies. We have also reported for the first time the release of a soluble form of Sig15 (sSig15), which we have demonstrated to circulate at higher levels in the plasma of pediatric B-ALL patients compared to healthy donors (Figure C, ****P≤0.0001). Detection of this sSig15 negatively correlated with circulating levels of IL-12 and IL-1α/β (Figure D, depicting correlations of cytokines using Pearson's r), suggesting sSig15 levels correspond to a systemically immunosuppressive phenotype. Flow cytometry of fresh pediatric B ALL cells demonstrates expression of surface Sig15 in a subset of cases. Thus, Sig15 has the capacity to promote immunosuppressive effects at both marrow-localized and systemic levels. Together, these results suggest Siglec-15 is a novel, potent immunosuppressive molecule active in leukemia progression that may be targeted therapeutically to activate T lymphocytes against leukemia cells. Figure 1 Figure 1. Disclosures Abukharma: NextCure Inc.: Current Employment. Liu: NextCure: Current Employment, Current holder of stock options in a privately-held company.

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Heterogeneity of T-cell lymphoblastic malignancies

Blood ◽

10.1182/blood.v55.5.806.bloodjournal555806 ◽

1980 ◽

Vol 55 (5) ◽

pp. 806-810

Author(s):

LM Nadler ◽

EL Reinherz ◽

HJ Weinstein ◽

CJ D'Orsi ◽

SF Schlossman

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Tumor Cells ◽

Human Peripheral Blood ◽

Lymphoblastic Leukemia ◽

Cell Subset ◽

Disease Process ◽

Suppressor Cells ◽

Lymphoblastic Lymphoma ◽

Cell Acute Lymphoblastic Leukemia

To determine the T-cell lineage of the malignant lymphoblast in lymphoblastic lymphoma, tumor cells from nine patients were phenotyped employing a T-cell subset specific heteroantisera, TH2. The normal human peripheral blood T-cell compartment is composed of 80% TH2- negative and 20% TH2-positive T cells, as defined by reactivity with subset specific heteroantisera. Human suppressor cells are TH2 reactive, whereas helper cells are TH2 unreactive. Tumor cells from the majority of patients with lymphoblastic lymphoma were TH2 reactive in contrast to the lack of reactivity previously described in the majority of patients with T-cell acute lymphoblastic leukemia. Comparative clinical studies, including disease presentation and course, were correlated with the presence of the TH2 antigen on the tumor cell. These results provide evidence to support the notion of heterogeneity in the T-lymphoblastic malignancies and suggest that lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia are probably not a single disease process.

Download Full-text