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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 1-3

The enigmatic cell of origin of chronic lymphocytic leukemia

1 Director Laboratory Services, Transfusion Medicine, and Research, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
2 Attending Consultant, Molecular Diagnostics, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India

Date of Submission21-Jul-2022
Date of Acceptance21-Jul-2022
Date of Web Publication02-Sep-2022

Correspondence Address:
Dr. Anurag Mehta
Director Laboratory Services, Transfusion Medicine, and Research, Sector 5 Rohini, Sir Chhotu Ram Marg, New Delhi 110085
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jco.jco_13_22

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How to cite this article:
Mehta A, Nathany S. The enigmatic cell of origin of chronic lymphocytic leukemia. J Curr Oncol 2022;5:1-3

How to cite this URL:
Mehta A, Nathany S. The enigmatic cell of origin of chronic lymphocytic leukemia. J Curr Oncol [serial online] 2022 [cited 2024 Feb 28];5:1-3. Available from: http://www.https://journalofcurrentoncology.org//text.asp?2022/5/1/1/355582

The quest to identify the normal counterpart of leukemia/lymphoma cells has been a pet pursuit of lymphoma biologists. In many instances, it has helped explain the biology of a disease. The classic example is diffuse large B-cell lymphoma (DLBCL).[1] The distinction in the cell of origin (COO) of germinal center B-cell-type DLBCL from activated B-cell-type DLBCL established the fundamental differences between the two subtypes in prognosis, response to treatment, and survival.[2]

Chronic lymphocytic leukemia (CLL) is leukemia with clonal expansion in bone marrow (BM), peripheral blood, and lymphoid organs of mature B cells with a unique phenotype expressing CD19, CD5, and CD23.[3] It has a highly variable disease course, ranging from a stable disease with almost average longevity to a rapidly progressive downhill course and an early death.[4] What is responsible for such stark differences in the clinical course? Can the COO explain these differences like in DLBCL?

The B cell develops from a common lymphoid precursor in the BM.[5] The pro-B cell is the first to differentiate, followed by the pre-B cell. A deviating differentiation at the pro-B-cell stage generates a B1-cell precursor. The pre-B cell shows the rearrangement of the IGHV (immunoglobulin heavy chain variable region) gene but lacks the rearrangement of the light-chain gene. The productive rearrangement of the light-chain gene allows the assembly of a B-cell receptor (BCR) and conversion into an immature B cell or B1 cell.[6] Immature B cells with autoreactive BCRs undergo clonal deletion, receptor editing of Ϗ/ƛ light-chain genes, and receptor revision of IGHV. Eventually, these immature B cells and their B1 counterparts are released into the periphery, take refuge in lymph nodes (LNs) and spleen, and go through a transitional B-cell or B1-cell ontogeny state before forming a B1 cell or marginal zone (MZ) B cells. Pursuing the same pathway, but with an additional T-cell stimulus, the transitional cells turn into follicular B cells. Each subsequent foreign antigen stimulation will yield a differently reactive B-cell population with a mutated or unmutated BCR and differing Ig classes [Figure 1].
Figure 1: An abridged view of B-cell development before foreign antigen stimulation. Note that B1 cells have not been identified in humans though analogous cells have been observed on serosal surfaces. This process of pre-foreign antigen-driven development of B cells yields three populations of B cells, namely, B1 cells, marginal zone B cells, and follicular B cells. The next panel (pink background) illustrates a condensed developmental ontogeny following activation by foreign antigen. The marginal zone cells are capable of developing into mutated, class-switched B-cell receptors

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Hypothetically, three cells are the likely candidates (a) MZ B cells, (b) a transitional B-cell, or (c) a human analog of a B-1-like cell. The MZ B cells can develop into u-CLL (unmutated IGHV CLL), and m-CLL (hypermutated IGHV CLL), show class switches, and have T-independent antigen–BCR interaction.[7] In addition, such interactions can be auto-reactive and polyreactive, simulating the BCR of CLL cells. Given these overwhelming proofs, the MZ B cell is the strongest putative candidate as the COO of CLL. Speaking in favor of a human analog of B-1 cell, these carry unmutated IGV gene and encode for polyreactive and autoreactive BCR to provide a quick response to repetitively patterned microbial antigens and cryptic antigens exposed following apoptosis. Furthermore, a B-1 cell CLL has been seen in mice supporting its candidature as the COO for human CLL. The B1 cell origin, however, may be called into question due to its inability to produce mCLL. Moreover, its human analog is still to be conclusively proven, although early evidence is emerging. The third candidate as the COO for CLL is the transitional B cell because it is CD5 +, carries autoreactive BCR, and shows both mutated and unmutated IGHV. Most significantly, it sits at the crossroad where a few evolutionary alterations can take it through T independent or T dependent– BCR interaction, mutated or unmutated pathway, and class switch[5] [Figure 1].

We have realized in preceding that antigen specificities of CLL BCRs are impartial to self or foreign antigens. This implies that CLL arises from a cell with autoreactive BCR or a BCR that has experienced a foreign antigen. Consequently, irrespective of antigenic experience, the normal counterpart is an antigen-experienced B cell. Having established that the COO of CLL is an antigen-experienced cell, the next question that begs to be answered is the stage at which this transforming event occurred in the B cell or B-cell precursor?

CLL has two subsets, one with hypermutated IGHV gene and the other with unmutated IGHV.[7] The hypermutated IGHV in CLL suggests a COO that has voyaged through the germinal center and is antigen-experienced. What about the uCLL? Does carrying an unmutated IGHV gene mean naivety to an antigenic experience? By 2012,[8] it was established that BCR rearrangement is stereotypical in approximately 20%–28% of CLL,[2] especially uCLL, with reactivity to a limited repertoire of polymicrobial and autoantigens.[9] The inference drawn from this observation is that even uCLL though unmutated, are antigen-experienced, responding to a limited set of antigen classes or epitopes, and have been preferentially selected for leukemic conversion. This implies that the COO of u-CLL, like one from m-CLL, is an antigen-experienced cell without undergoing a germinal center journey and associated hypermutation of BCR.[10]

The theorized difference between uCLL and mCLL seems irreconcilable, and a COO is expected to be distinct for each supporting a dual COO theory. However, extensive genomic and epigenomic studies have shown that the COOs of CLL are similar to antigen-experienced, memory-like normal B-lymphocytes with minimal differences in the gene expressions of u-CLL and m-CLL.[11] This observation points toward a single COO with some microenvironmental and other extraneous factors causing the clinical and biological divergence between u-CLL and m-CLL.

However, memory-like B cells seem a likely COO, as mentioned above. The other possible candidates have been a transitional B-cell and a human analog of a B-1-like cell. Believing that ontogeny repeats phylogeny, a more precise understanding may emerge from studying B-cell ontogeny to identify the best phylogenetic match amongst the three candidates for CLL.

In summary, despite expression studies pointing towards a single COO, synthesizing the current knowledge of B-cell ontogeny, a multiple normal counterpart model of CLL is more likely. We contend that a human B-1-cell analog gives rise to u-CLL with polyreactive BCRs and stereotypy, whereas transitional and MZ B cells are a COO of u-CLL without stereotypy. The m-CLL is most possibly derived from MZ cells or follicular cells that have traversed the germinal center and developed into MZ memory B cells.

Despite the ongoing efforts, no single COO can be assigned to CLL. Rapidly emerging new techniques in genomics and epigenomics may provide horizontal genomic profiles and answer the question of COO in CLL and its relation to the divergent clinical course of CLL. It seems acceptable to look into the other molecular and cytogenetic markers to predict and select therapies. We shall discuss many less contentious issues in this volume of the Journal of Current Oncology.


Mr. Karan Kumar is duly acknowledged for his invaluable contributions to creating the editorial figure.

Financial support and sponsorship

Not applicable.

Conflicts of interest

There are no conflicts of interest.

  References Top

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Shiozawa E Chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL). J Showa Med Assoc 2008;68: 269-71.  Back to cited text no. 2
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Zenz T, Gribben JG, Hallek M, Döhner H, Keating MJ, Stilgenbauer S Risk categories and refractory CLL in the era of chemoimmunotherapy. Blood 2012;119:4101-7.  Back to cited text no. 4
Hentges F B lymphocyte ontogeny and immunoglobulin production. Clin Exp Immunol 1994;97:3-9.  Back to cited text no. 5
Colombo M, Cutrona G, Reverberi D, Fabris S, Neri A, Fabbi M, et al. Intraclonal cell expansion and selection driven by B cell receptor in chronic lymphocytic leukemia. Mol Med 2011;17:834-9.  Back to cited text no. 6
Gupta SK, Viswanatha DS, Patel KP Evaluation of somatic hypermutation status in chronic lymphocytic leukemia (CLL) in the era of next generation sequencing. Front Cell Dev Biol 2020;8:357.  Back to cited text no. 7
Herbaux C, Duployez N, Badens C, Poret N, Gardin C, Decamp M, et al; GFM (Groupe Francophone des Myelodysplasies). Incidence of Atrx mutations in myelodysplastic syndromes, the value of microcytosis. Am J Hematol 2015;90:737-8.  Back to cited text no. 8
Stamatopoulos K, Belessi C, Moreno C, Boudjograh M, Guida G, Smilevska T, et al. Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: Pathogenetic implications and clinical correlations. Blood 2007;109:259-70.  Back to cited text no. 9
Darwiche W, Gubler B, Marolleau JP, Ghamlouch H Chronic lymphocytic leukemia B-cell normal cellular counterpart: Clues from a functional perspective. Front Immunol 2018;9: 683.  Back to cited text no. 10
Gaidano G, Foà R, Dalla-Favera R Molecular pathogenesis of chronic lymphocytic leukemia. J Clin Invest 2012;122: 3432-8.  Back to cited text no. 11


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