Molecular characterization of Novel ATM fusions in chronic lymphocytic leukemia and T-cell prolymphocytic leukemia

2021 ◽  
pp. 1-11
Author(s):  
Rashmi Kanagal-Shamanna ◽  
Haiyan Bao ◽  
Hutton Kearney ◽  
Stephanie Smoley ◽  
Zhenya Tang ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Molecular Characterization ◽  
Lymphocytic Leukemia ◽  
Prolymphocytic Leukemia

scholarly journals Rearrangement and expression of T cell antigen receptor genes in B cell chronic lymphocytic leukemia

Blood ◽  
1988 ◽  
Vol 71 (1) ◽  
pp. 178-185
Author(s):  
JD Norton ◽  
J Pattinson ◽  
AV Hoffbrand ◽  
H Jani ◽  
JC Yaxley ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Germ Line ◽  
Lymphocytic Leukemia ◽  
Gene Transcript ◽  
Prolymphocytic Leukemia ◽  
Beta 2 ◽  
Beta Gene ◽  
Cell Chronic Lymphocytic Leukemia

Fifty-nine patients with B cell chronic lymphocytic leukemia (B-CLL) were screened for clonal rearrangement of T cell receptor (TCR) beta and gamma chain genes. Four were found with rearranged TCR beta genes, but none had detectable rearrangement of TCR gamma genes. One typical patient with B-CLL had a TCR beta gene structure consistent with a variable-diversity-joining rearrangement into the C beta 2 gene on one allele. An apparently identical rearrangement pattern was seen in a second patient, which suggested that there may be a restriction on the repertoire of possible TCR beta gene recombinations in mature B cells. Two further patients had a simple deletion of sequences, consistent with a diversity-joining rearrangement into C beta 2 on one allele. All four patients had rearrangements of immunoglobulin heavy- and light- chain genes typical of mature B cell malignancies. However, on review of clinical, morphological, and immunophenotype data, two had features consistent with B cell prolymphocytic leukemia or B lymphoma, and a third had progressed to a prolymphocytic transformation. Low-level expression of a predominantly 1.0- to 1.2-kilobase germ line TCR beta gene transcript was detected in several B-CLLs and at a comparable level in the four with rearranged TCR beta genes. This, together with the low frequency of TCR gene rearrangement, suggests that most B-CLL cases arise at a developmental stage when factors required for TCR gene activity are not operative.

scholarly journals True T-cell chronic lymphocytic leukemia: a morphologic and immunophenotypic study of 25 cases [see comments]

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1163-1169 ◽  
Author(s):  
JD Hoyer ◽  
CW Ross ◽  
CY Li ◽  
TE Witzig ◽  
RD Gascoyne ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Wide Spectrum ◽  
Minor Component ◽  
Skin Lesions ◽  
Lymphocytic Leukemia ◽  
Prolymphocytic Leukemia ◽  
Male Predominance ◽  
A Minor ◽  
Cell Chronic Lymphocytic Leukemia

Abstract We studied 25 T-cell chronic lymphocytic leukemia (T-CLL) cases collected over a 15-year period. Immunophenotypic analysis was performed in each case; 12 cases were evaluated by cytogenetics, and gene rearrangement studies were performed in 14 cases. The median age was 57 years with a male predominance (M:F, 15:10). The median presenting lymphocyte count was 36.3 x 10(9)/L (range, 3.9 to 438 x 10(9)/L). Fourteen patients (56%) had shotty adenopathy and ten (40%) had mild-to-moderate splenomegaly at presentation; four (16%) had erythematous skin lesions. The lymphocytes were predominantly small; some cases had a minor component of medium-sized cells (< 10%). The nuclear: cytoplasmic ratios were uniformly high with round to oval nuclei; however, a wide spectrum of nuclear outlines could be found, ranging from minimally to markedly convoluted. Nucleoli were either absent or small and inconspicuous. These lymphocytes did not have the morphology of prolymphocytes and did not contain cytoplasmic granules. Bone marrow infiltration was generally in an interstitial pattern; the degree of involvement ranged from 15% to 90%. Immunophenotyping showed that the lymphocytes were mature T-cells with a predominant CD4+ immunophenotype. Three cases displayed a CD8+ immunophenotype. The patients were treated with a variety of chemotherapeutic regimens with only a minimal response observed in two of 20 patients. We conclude that T-CLL is an uncommon chronic lymphoproliferative disorder (CLPD) that can be morphologically similar to B-CLL, is distinct from T- prolymphocytic leukemia, and has an aggressive clinical course that is refractory to therapy. It may also be difficult to distinguish T-CLL from other T-CLPD, especially the leukemic phase of peripheral T-cell lymphoma and some cases of Sezary syndrome.

scholarly journals Rearrangement and expression of T cell antigen receptor genes in B cell chronic lymphocytic leukemia

Blood ◽  
1988 ◽  
Vol 71 (1) ◽  
pp. 178-185 ◽  
Author(s):  
JD Norton ◽  
J Pattinson ◽  
AV Hoffbrand ◽  
H Jani ◽  
JC Yaxley ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Germ Line ◽  
Lymphocytic Leukemia ◽  
Gene Transcript ◽  
Prolymphocytic Leukemia ◽  
Beta 2 ◽  
Beta Gene ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Fifty-nine patients with B cell chronic lymphocytic leukemia (B-CLL) were screened for clonal rearrangement of T cell receptor (TCR) beta and gamma chain genes. Four were found with rearranged TCR beta genes, but none had detectable rearrangement of TCR gamma genes. One typical patient with B-CLL had a TCR beta gene structure consistent with a variable-diversity-joining rearrangement into the C beta 2 gene on one allele. An apparently identical rearrangement pattern was seen in a second patient, which suggested that there may be a restriction on the repertoire of possible TCR beta gene recombinations in mature B cells. Two further patients had a simple deletion of sequences, consistent with a diversity-joining rearrangement into C beta 2 on one allele. All four patients had rearrangements of immunoglobulin heavy- and light- chain genes typical of mature B cell malignancies. However, on review of clinical, morphological, and immunophenotype data, two had features consistent with B cell prolymphocytic leukemia or B lymphoma, and a third had progressed to a prolymphocytic transformation. Low-level expression of a predominantly 1.0- to 1.2-kilobase germ line TCR beta gene transcript was detected in several B-CLLs and at a comparable level in the four with rearranged TCR beta genes. This, together with the low frequency of TCR gene rearrangement, suggests that most B-CLL cases arise at a developmental stage when factors required for TCR gene activity are not operative.

scholarly journals Composite Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and T-Prolymphocytic Leukemia Presenting with Lymphocytosis, Skin Lesions, and Generalized Lymphadenopathy

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Ali Sakhdari ◽  
Guilin Tang ◽  
Lawrence E. Ginsberg ◽  
Cheryl F. Hirsch-Ginsberg ◽  
Carlos E. Bueso-Ramos ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Clinical Course ◽  
Skin Lesions ◽  
Lymphocytic Leukemia ◽  
Rare Type ◽  
Prolymphocytic Leukemia ◽  
High Relapse Rate ◽  
Dismal Prognosis ◽  
Generalized Lymphadenopathy

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries with an incidence of 3-5 cases per 100,000 persons. Most patients follow an indolent clinical course with eventual progression and need for therapy. In contrast, T-prolymphocytic leukemia (T-PLL) is a rare type of T-cell leukemia with most patients having an aggressive clinical course and a dismal prognosis. Therapies are limited for T-PLL patients and there is a high relapse rate. Morphologically, the cells of CLL and T-PLL can show overlapping features. Here, we report the case of a 61-year-old man who presented with a clinically indolent CLL and T-PLL, initially diagnosed solely and followed as CLL, despite the presence of an associated but unrecognized aberrant T-cell population in blood. After 2 years, the T-PLL component became more apparent with cutaneous and hematologic manifestations and the diagnosis was confirmed by immunophenotypic and cytogenetic analysis. Fluorescencein situhybridization demonstrated anATMdeletion in both CLL and T-PLL components. Retrospective testing demonstrated that composite CLL and T-PLL were both present in skin and lymph nodes as well as in blood and bone marrow since initial presentation. This case is also unique because it highlights that a subset of T-PLL patients can present with clinically indolent disease. The concomitant detection ofATMmutation in CLL and T-PLL components raises the possibility of a common pathogenic mechanism.

Marrow Stromal Cells Induce TCL1 Expression in Chronic Lymphocytic Leukemia B Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2347-2347
Author(s):  
Mariela Sivina ◽  
Elena Hartmann ◽  
Michael Keating ◽  
William G Wierda ◽  
Andreas Rosenwald ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Stromal Cells ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Marrow Stromal Cells ◽  
Immunoglobulin Gene ◽  
Prolymphocytic Leukemia

Abstract Abstract 2347 Poster Board II-324 The human T cell leukemia/lymphoma 1 (TCL1) oncogene was initially identified as a target of chromosomal translocations and inversions at the 14q32.1 chromosome breakpoint region in T-cell prolymphocytic leukemia (T-PLL). Increased TCL1 expression is seen in follicular lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia (CLL). Transgenic mice over-expressing TCL1 under control of the mu immunoglobulin gene enhancer develop a CD5+ B cell lymphoproliferative disorder that mimics human CLL, indicating that TCL1 plays a central and/or causal role in the pathogenesis of CLL. However, chromosome aberrations that constitutively activate TCL1 have not (yet) been identified in the vast majority of CLL patients, and therefore the oncogenic mechanism(s) of TCL1 activation in CLL remain unclear. There is growing evidence that external signals from the microenvironment control and regulate the survival and proliferation of CLL cells. Marrow stromal cells (MSC) are highly effective in protecting CLL cells from spontaneous and drug-induced apoptosis, and are used as a model system to study the marrow microenvironment. In order to explore the molecular cross talk between CLL cells and MSC, we co-cultured CLL cells with different MSC and analyzed gene expression changes induced by co-cultures with MSC, an approach similar to our recent study with nurselike cells (Blood 113:3050-8, 2009). For this, RNA was extracted from 19-purified CLL cells from 10 different patients (baseline expression, day 0). Also, the same patients' samples were co-cultured on stroma cells (KUSA-H1, NK-Tert) for 2 and 7 days. At these time points, RNA again was isolated after CD19-purification. Then, gene expression was determined using HG U133 plus 2.0 oligonucleotide arrays from Affymetrix. Gene expression changes were analyzed in individual patients' samples, comparing baseline samples' gene expression to samples after 2 and 7 of co-culture on MSC. We observed relatively homogeneous gene expression changes in CLL cells after co-culture with MSC. We found that TCL1 was among the top 5 genes that were most highly up-regulated by MSC, based on at least 3-fold up-regulation in at least 6 of the paired samples. We also found an up-regulation of TCL1 at the protein level when assessed by immunoblotting and flow cytometry in CLL samples after co-culture with MSC. These findings indicate that MSC can induce and regulate TCL1 expression in CLL, suggesting that the microenvironment plays an even greater role in the pathogenesis of this disease than previously recognized. Disclosures: No relevant conflicts of interest to declare.

scholarly journals True T-cell chronic lymphocytic leukemia: a morphologic and immunophenotypic study of 25 cases [see comments]

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 1163-1169 ◽  
Author(s):  
JD Hoyer ◽  
CW Ross ◽  
CY Li ◽  
TE Witzig ◽  
RD Gascoyne ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Wide Spectrum ◽  
Minor Component ◽  
Skin Lesions ◽  
Lymphocytic Leukemia ◽  
Prolymphocytic Leukemia ◽  
Male Predominance ◽  
A Minor ◽  
Cell Chronic Lymphocytic Leukemia

We studied 25 T-cell chronic lymphocytic leukemia (T-CLL) cases collected over a 15-year period. Immunophenotypic analysis was performed in each case; 12 cases were evaluated by cytogenetics, and gene rearrangement studies were performed in 14 cases. The median age was 57 years with a male predominance (M:F, 15:10). The median presenting lymphocyte count was 36.3 x 10(9)/L (range, 3.9 to 438 x 10(9)/L). Fourteen patients (56%) had shotty adenopathy and ten (40%) had mild-to-moderate splenomegaly at presentation; four (16%) had erythematous skin lesions. The lymphocytes were predominantly small; some cases had a minor component of medium-sized cells (< 10%). The nuclear: cytoplasmic ratios were uniformly high with round to oval nuclei; however, a wide spectrum of nuclear outlines could be found, ranging from minimally to markedly convoluted. Nucleoli were either absent or small and inconspicuous. These lymphocytes did not have the morphology of prolymphocytes and did not contain cytoplasmic granules. Bone marrow infiltration was generally in an interstitial pattern; the degree of involvement ranged from 15% to 90%. Immunophenotyping showed that the lymphocytes were mature T-cells with a predominant CD4+ immunophenotype. Three cases displayed a CD8+ immunophenotype. The patients were treated with a variety of chemotherapeutic regimens with only a minimal response observed in two of 20 patients. We conclude that T-CLL is an uncommon chronic lymphoproliferative disorder (CLPD) that can be morphologically similar to B-CLL, is distinct from T- prolymphocytic leukemia, and has an aggressive clinical course that is refractory to therapy. It may also be difficult to distinguish T-CLL from other T-CLPD, especially the leukemic phase of peripheral T-cell lymphoma and some cases of Sezary syndrome.

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