Chronic Lymphocytic Leukemia

Chiorazzi, Nicholas; Chen, Shih‐Shih; Kanti, R.

doi:10.1101/cshperspect.a035220

Cited by 38 publications

(41 citation statements)

References 382 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast with these in vivo features, apoptosis occurs after in vitro culture, suggesting an important role of the microenvironment on CLL cell survival ( 138 , 139 ). CLL is the prototype of a cancer where both genetic and microenvironmental factors promote the onset, expansion, and progression of the disease ( 140 , 141 ). Although classically CLL was considered a disease of accumulation, new data indicate that CLL expansion is a dynamic process in which cell proliferation compensates for the cell loss from death ( 142 , 143 ) and that accumulation of the malignant cells reflects a balance between the effects of cell proliferation and death ( 144 ).…”

Section: Chronic Lymphocytic Leukemia: the Role Of Microenvironmentalmentioning

confidence: 99%

AID in Chronic Lymphocytic Leukemia: Induction and Action During Disease Progression

2021

Self Cite

View full text Add to dashboard Cite

The enzyme activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin (Ig) genes, critical actions for an effective adaptive immune response. However, in addition to the benefits generated by its physiological roles, AID is an etiological factor for the development of human and murine leukemias and lymphomas. This review highlights the pathological role of AID and the consequences of its actions on the development, progression, and therapeutic refractoriness of chronic lymphocytic leukemia (CLL) as a model disease for mature lymphoid malignancies. First, we summarize pertinent aspects of the expression and function of AID in normal B lymphocytes. Then, we assess putative causes for AID expression in leukemic cells emphasizing the role of an activated microenvironment. Thirdly, we discuss the role of AID in lymphomagenesis, in light of recent data obtained by NGS analyses on the genomic landscape of leukemia and lymphomas, concentrating on the frequency of AID signatures in these cancers and correlating previously described tumor-gene drivers with the presence of AID off-target mutations. Finally, we discuss how these changes could affect tumor suppressor and proto-oncogene targets and how they could be associated with disease progression. Collectively, we hope that these sections will help to better understand the complex paradox between the physiological role of AID in adaptive immunity and its potential causative activity in B-cell malignancies.

show abstract

Section: Chronic Lymphocytic Leukemia: the Role Of Microenvironmentalmentioning

confidence: 99%

AID in Chronic Lymphocytic Leukemia: Induction and Action During Disease Progression

2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Chronic lymphocytic leukemia (CLL) is a common, incurable adult hematologic disease of unknown etiology [ 1 – 3 ]. Although the majority of circulating CLL cells are not replicating, a small fraction divides in lymphoid tissues and some of the recently divided leukemic cells migrate and are found in peripheral blood (PB) [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Musashi 2 influences chronic lymphocytic leukemia cell survival and growth making it a potential therapeutic target

et al. 2021

Self Cite

View full text Add to dashboard Cite

Progression of chronic lymphocytic leukemia (CLL) results from the expansion of a small fraction of proliferating leukemic B cells. When comparing the global gene expression of recently divided CLL cells with that of previously divided cells, we found higher levels of genes involved in regulating gene expression. One of these was the oncogene Musashi 2 (MSI2), an RNA-binding protein that induces or represses translation. While there is an established role for MSI2 in normal and malignant stem cells, much less is known about its expression and role in CLL. Here we report for the first time ex vivo and in vitro experiments that MSI2 protein levels are higher in dividing and recently divided leukemic cells and that downregulating MSI2 expression or blocking its function eliminates primary human and murine CLL and mature myeloid cells. Notably, mature T cells and hematopoietic stem and progenitor cells are not affected. We also confirm that higher MSI2 levels correlate with poor outcome markers, shorter time-to-first-treatment, and overall survival. Thus, our data highlight an important role for MSI2 in CLL-cell survival and proliferation and associate MSI2 with poor prognosis in CLL patients. Collectively, these findings pinpoint MSI2 as a potentially valuable therapeutic target in CLL.

show abstract

“…1,2 In 2020, the Surveillance, Epidemiology and End Result program (SEER) database estimated 21,040 new cases of CLL in the United States with 4060 deaths attributed to this disease. 3 This translates into an incidence of CLL in the United States of approximately 5.0 per 100,000 men or women with a lifetime risk of 0.6%. CLL is largely considered a disease of the elderly with a median age at diagnosis of 70 and affects men approximately twice as often as women.…”

Section: Introductionmentioning

confidence: 99%

“…CLL is largely considered a disease of the elderly with a median age at diagnosis of 70 and affects men approximately twice as often as women. 3 While several novel therapies have been developed for the treatment of CLL in recent years, most patients with CLL ultimately progress or relapse requiring therapy. 4,5 The natural history of CLL/SLL is variable and outcomes are influenced by patient characteristics, clinical factors at the time of diagnosis, and the genetics of the tumor.…”

Section: Introductionmentioning

confidence: 99%

Oral PI3K-δ,γ Inhibitor for the Management of People with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: A Narrative Review on Duvelisib

Shah¹,

Barrientos²

2021

OTT

View full text Add to dashboard Cite

The development of highly effective targeted therapies has led to a new treatment paradigm in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). Despite these advances, many patients will eventually require alternative treatment strategies due to the emergence of tolerability issues or resistance to these novel agents. Duvelisib is a first-in-class, potent oral agent with dual inhibitor activity against the δ and γ isoforms of phosphoinositide 3-kinase (PI3Kδ and PI3Kγ), which are specific to the hematopoietic system. Dysregulation of the PI3K/PTEN/AKT/mTOR pathway has been implicated in cancer cell growth, survival and metabolism and has been the subject of cancer drug development in recent years. Duvelisib demonstrated activity in CLL/SLL in early trials, leading to further evaluation in the Phase 3 DUO trial that compared duvelisib against ofatumumab in patients with relapsed/refractory CLL/SLL. This trial led to the Food and Drug Administration (FDA) approval for the treatment of adult patients with CLL/SLL after at least two prior lines of therapy. The major reason for therapy discontinuation is the development of serious adverse events, which include severe infections and diarrhea/colitis, precluding its widespread use. Ongoing clinical trials are evaluating duvelisib in combination strategies and with alternate dosing schedules in patients with CLL/SLL. With close monitoring, duvelisib can be a promising drug for the treatment of patients with relapsed or refractory CLL/SLL. This review summarizes the relevant clinical data from recent clinical advances in CLL and aims to interpret the duvelisib trials while exploring strategies to improve its use and adverse event management in the era of novel targeted agents.

show abstract

Chronic Lymphocytic Leukemia

Abstract: Stereotyped subset-biased acquisition of recurrent gene mutations. MYD88 and BIRC3 mutations are rare in all subsets.

Cited by 38 publications

References 382 publications

AID in Chronic Lymphocytic Leukemia: Induction and Action During Disease Progression

AID in Chronic Lymphocytic Leukemia: Induction and Action During Disease Progression

Musashi 2 influences chronic lymphocytic leukemia cell survival and growth making it a potential therapeutic target

Oral PI3K-δ,γ Inhibitor for the Management of People with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: A Narrative Review on Duvelisib

Contact Info

Product

Resources

About