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{{Chronic lymphocytic leukemia}}
{{Chronic lymphocytic leukemia}}


{{CMG}}; {{AE}} {{RT}}
{{CMG}} {{AE}} {{S.S}} {{HL}}


==Overview==
==Overview==
Chronic lymphocytic leukemia arises from pre-follicular, center [[B cell]]s, that are normally involved in the process of human [[immunoglobulin]] production. Development of chronic lymphocytic leukemia is the result of multiple [[genetic mutation]]s that promote both [[malignant]] leukemic [[proliferation]] and [[apoptotic]] [[resistance]] of mature [[B cells]]. Structural [[genetic mutation]]s involved in the [[pathogenesis]] of chronic lymphocytic leukemia include [[chromosome]] 13q deletion, [[chromosome 17]]<nowiki/>p deletion, and [[chromosome 11]]<nowiki/>q deletion. On [[microscopic]] [[histopathological]] analysis, characteristic findings of chronic lymphocytic leukemia include small [[lymphoid]] cells, thin [[cytoplasmic]] border, lack of [[nucleolus]], and the presence of [[Smudge cells|smudge]] cells.


==Pathophysiology==
CLL affects a particular lymphocyte, the [[B cell]], which originates in the bone marrow, develops in the lymph nodes, and normally fights infection. In CLL, the DNA of a B cell is damaged, so that it can't fight infection, but it grows out of control and crowds out the healthy blood cells that can fight infection.


CLL is an abnormal neoplastic proliferation of B cells. The cells accumulate mainly in the bone marrow and blood. CLL is closely related to a disease called [[small lymphocytic lymphoma]] (SLL), a type of [[non-Hodgkin's lymphoma]] which presents primarily in the [[lymph nodes]]. The [[World Health Organization]] considers CLL and SLL to be "one disease at different stages, not two separate entities".<ref name="pmid10577857">{{cite journal |author=Harris NL, Jaffe ES, Diebold J, ''et al'' |title=World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997 |journal=J. Clin. Oncol. |volume=17 |issue=12 |pages=3835-49 |year=1999 |pmid=10577857 |doi=}}</ref>
==Pathogenesis==
*The pathology of chronic lymphocytic leukemia can be understood as follows:<ref name="pmid23561469">{{cite journal |vauthors=Herishanu Y, Katz BZ, Lipsky A, Wiestner A |title=Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications |journal=Hematol. Oncol. Clin. North Am. |volume=27 |issue=2 |pages=173–206 |date=April 2013 |pmid=23561469 |doi=10.1016/j.hoc.2013.01.002 |url=}}</ref><ref name="pmid235614692">{{cite journal |vauthors=Herishanu Y, Katz BZ, Lipsky A, Wiestner A |title=Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications |journal=Hematol. Oncol. Clin. North Am. |volume=27 |issue=2 |pages=173–206 |date=April 2013 |pmid=23561469 |doi=10.1016/j.hoc.2013.01.002 |url=}}</ref><ref name="pmid26065657">{{cite journal |vauthors=Strati P, Shanafelt TD |title=Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification |journal=Blood |volume=126 |issue=4 |pages=454–62 |date=July 2015 |pmid=26065657 |doi=10.1182/blood-2015-02-585059 |url=}}</ref><ref name="GhiaCaligaris-Cappio2012">{{cite journal|last1=Ghia|first1=P.|last2=Caligaris-Cappio|first2=F.|title=Monoclonal B-cell lymphocytosis: right track or red herring?|journal=Blood|volume=119|issue=19|year=2012|pages=4358–4362|issn=0006-4971|doi=10.1182/blood-2012-01-404681}}</ref><ref name="PuenteJares2018">{{cite journal|last1=Puente|first1=Xose S.|last2=Jares|first2=Pedro|last3=Campo|first3=Elias|title=Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions|journal=Blood|volume=131|issue=21|year=2018|pages=2283–2296|issn=0006-4971|doi=10.1182/blood-2017-10-764373}}</ref><ref name="pmid23413591">{{cite journal |vauthors=Jain P, O'Brien S |title=Richter's transformation in chronic lymphocytic leukemia |journal=Oncology (Williston Park, N.Y.) |volume=26 |issue=12 |pages=1146–52 |date=December 2012 |pmid=23413591 |doi= |url=}}</ref><ref name="pmid234135912">{{cite journal |vauthors=Jain P, O'Brien S |title=Richter's transformation in chronic lymphocytic leukemia |journal=Oncology (Williston Park, N.Y.) |volume=26 |issue=12 |pages=1146–52 |date=December 2012 |pmid=23413591 |doi= |url=}}</ref>
**Chronic lymphocytic leukemia is defined as clonal [[proliferation]] of incompetent [[B-cells]].
**Chronic lymphocytic leukemia arises from pre-follicular, center [[B cell]]s that are normally involved in the process of [[human]] [[immunoglobulin]]s production.
**Chronic lymphocytic leukemia [[Cell (biology)|cells]] are clonal [[B cells]], and their [[differentiation]] is halted between the pre-[[B cell|B cells]] and mature [[B cell|B cells]].
**Pre-[[malignant]] [[B cell]] [[proliferation]] precedes chronic lymphocytic leukemia/[[SLL|small lymphocytic leukemia]] and is known as [[Monoclonal B-cell lymphocytosis|monoclonal B cell lymphocytosis]] ([[Monoclonal B-cell lymphocytosis|MBL]]).
**There are multiple factors leading to production of [[Monoclonal B-cell lymphocytosis|MBL]], which involves [[antigen]] stimulation, [[gene]] [[mutation]], environment factors, [[Immunology|immunologic]] and [[Cytogenetics|cytogenetic]] [[Modifications (genetics)|modifications]].
**Repeated results from these factors lead to advancement of [[Monoclonal B-cell lymphocytosis|MBL]] to chronic lymphocytic leukemia.
**Most of the [[Patient|patients]] of chronic lymphocytic leukemia are asymptomatic, until the incompetent [[lymphocytes]] start to accumulate and infiltrate organ systems.
**[[Malignant]] [[lymphocytic]] [[Cell (biology)|cells]] infiltrate [[hematopoietic]] sites, such as the [[bone marrow]], where they [[Interference theory|interfere]] with the production of [[red blood cell]]s and [[platelet]]s.
**Chronic lymphocytic leukemia may also infiltrate the [[lymph node]]s, [[spleen]], and [[liver]].
**[[Immune deficiency]] may occur in chronic lymphocytic leukemia as the majority of cases develop [[hypogammaglobulinemia]].
**[[Warm autoimmune hemolytic anemia]] may develop due to the production of [[IgA]] and [[IgG]] [[autoantibodies]] among certain cases of chronic lymphocytic anemia.
**[[Autoimmune]] [[thrombocytopenia]] may develop due to the production of [[autoantibodies|auto-antibodies]].
**Production of [[cytokine]]s, [[angiogenic]] factors, and [[chemokine]]s by the surrounding [[macrophage]]s and [[T cell]]s provide important stimuli for [[malignant]] [[B cell]]s proliferation in chronic lymphocytic leukemia.
**[[Richter's transformation]] represents the conversion of chronic lymphocytic leukemia into a more aggressive and rapidly growing [[large B cell lymphoma]].
**[[Richter's transformation]] may occur among 1-5% of chronic lymphocytic leukemia cases.


In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, it is now recognized that these so-called T-cell CLLs are in fact a separate disease group and are currently classified as [[T-cell prolymphocytic leukemia]]s.
==Immunology==
* Chronic lymphocytic leukemia cells express [[B cell]] surface [[Antigen|antigens]] such as [[CD19]], [[CD20]], [[CD21]] and [[CD23]] [[monoclonal antibodies]].<ref name="pmid1532590">{{cite journal |vauthors=Fournier S, Delespesse G, Rubio M, Biron G, Sarfati M |title=CD23 antigen regulation and signaling in chronic lymphocytic leukemia |journal=J. Clin. Invest. |volume=89 |issue=4 |pages=1312–21 |date=April 1992 |pmid=1532590 |pmc=442993 |doi=10.1172/JCI115717 |url=}}</ref><ref name="pmid1717071">{{cite journal |vauthors=Geisler CH, Larsen JK, Hansen NE, Hansen MM, Christensen BE, Lund B, Nielsen H, Plesner T, Thorling K, Andersen E |title=Prognostic importance of flow cytometric immunophenotyping of 540 consecutive patients with B-cell chronic lymphocytic leukemia |journal=Blood |volume=78 |issue=7 |pages=1795–802 |date=October 1991 |pmid=1717071 |doi= |url=}}</ref>
* They also express [[CD5]], which is a [[T cell]] [[antibody]].<ref name="pmid30407619">{{cite journal |vauthors=Friedman DR, Guadalupe E, Volkheimer A, Moore JO, Weinberg JB |title=Clinical outcomes in chronic lymphocytic leukaemia associated with expression of CD5, a negative regulator of B-cell receptor signalling |journal=Br. J. Haematol. |volume=183 |issue=5 |pages=747–754 |date=December 2018 |pmid=30407619 |doi=10.1111/bjh.15632 |url=}}</ref>
* Chronic lymphocytic leukemia cells also express decreased level of [[B cell]] surface [[Antigen|antigens]] [[IgM]] and [[Immunoglobulin D|IgD]] [[immunoglobulin]].<ref name="pmid27542958">{{cite journal |vauthors=Haerzschel A, Catusse J, Hutterer E, Paunovic M, Zirlik K, Eibel H, Krenn PW, Hartmann TN, Burger M |title=BCR and chemokine responses upon anti-IgM and anti-IgD stimulation in chronic lymphocytic leukaemia |journal=Ann. Hematol. |volume=95 |issue=12 |pages=1979–1988 |date=December 2016 |pmid=27542958 |pmc=5093209 |doi=10.1007/s00277-016-2788-6 |url=}}</ref>
*
==Cytogenetics==
* Development of chronic lymphocytic leukemia is the result of multiple [[genetic mutation]]s that promote both [[malignant]] leukemic proliferation and [[apoptotic]] resistance of mature [[B cell]]s.
* Structural [[genetic mutations]] and associated features involved in the [[pathogenesis]] of chronic lymphocytic leukemia include:<ref name="pmid9116297">{{cite journal |vauthors=Döhner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M, Fischer K, Hunstein W, Lichter P |title=11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis |journal=Blood |volume=89 |issue=7 |pages=2516–22 |date=April 1997 |pmid=9116297 |doi= |url=}}</ref><ref name="pmid11136261">{{cite journal |vauthors=Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P |title=Genomic aberrations and survival in chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=343 |issue=26 |pages=1910–6 |date=December 2000 |pmid=11136261 |doi=10.1056/NEJM200012283432602 |url=}}</ref><ref name="pmid111362612">{{cite journal |vauthors=Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P |title=Genomic aberrations and survival in chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=343 |issue=26 |pages=1910–6 |date=December 2000 |pmid=11136261 |doi=10.1056/NEJM200012283432602 |url=}}</ref><ref name="pmid26316624">{{cite journal |vauthors=Guièze R, Robbe P, Clifford R, de Guibert S, Pereira B, Timbs A, Dilhuydy MS, Cabes M, Ysebaert L, Burns A, Nguyen-Khac F, Davi F, Véronèse L, Combes P, Le Garff-Tavernier M, Leblond V, Merle-Béral H, Alsolami R, Hamblin A, Mason J, Pettitt A, Hillmen P, Taylor J, Knight SJ, Tournilhac O, Schuh A |title=Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL |journal=Blood |volume=126 |issue=18 |pages=2110–7 |date=October 2015 |pmid=26316624 |doi=10.1182/blood-2015-05-647578 |url=}}</ref><ref name="pmid8892671">{{cite journal |vauthors=Garcìa-Marco JA, Price CM, Ellis J, Morey M, Matutes E, Lens D, Colman S, Catovsky D |title=Correlation of trisomy 12 with proliferating cells by combined immunocytochemistry and fluorescence in situ hybridization in chronic lymphocytic leukemia |journal=Leukemia |volume=10 |issue=11 |pages=1705–11 |date=November 1996 |pmid=8892671 |doi= |url=}}</ref>
**[[Chromosome 11]] long arm [[Deletion (genetics)|deletion]] (11q22-q23):
***Relapsing [[disease]], [[refractory]] to initial [[therapy]], poor [[prognosis]], large-scale [[lymph node]] involvement and shorter survival
**[[Chromosome 13]] long arm [[Deletion (genetics)|deletion]] (most common [[Genetics|genetic]] [[mutation]]):
***Better prognosis
**<nowiki/>[[Chromosome 17]]<nowiki/>p13 [[Deletion (genetics)|deletion]]:
***[[Tumor]] suppressor [[gene]] [[TP53]] [[Deletion (genetics)|deletion]], relapsing [[disease]] and refractory to initial [[therapy]] 
**[[Trisomy]] 12:
***<nowiki/>Increased [[proliferation]] and advanced [[disease]]


[[Acute lymphocytic leukemia]] (ALL) is a disease of children, but CLL is a disease of adults. Most (>75%) people newly diagnosed with CLL are over age 50, and two-thirds are men. In the United States during 2007, it is estimated there will be 15,340 new cases diagnosed and 4,500 deaths<ref name="NCI-CLL-page1">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page1 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: General Information |author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>, but because of prolonged survival, many more people are living with CLL.
==Molecular Genetics==
* [[Somatic]] [[Genetics|genetic]] [[Mutation|mutations]] and associated factors involved in the [[pathogenesis]] of chronic lymphocytic leukemia include:<ref name="pmid22150006">{{cite journal |vauthors=Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, Werner L, Sivachenko A, DeLuca DS, Zhang L, Zhang W, Vartanov AR, Fernandes SM, Goldstein NR, Folco EG, Cibulskis K, Tesar B, Sievers QL, Shefler E, Gabriel S, Hacohen N, Reed R, Meyerson M, Golub TR, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ |title=SF3B1 and other novel cancer genes in chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=365 |issue=26 |pages=2497–506 |date=December 2011 |pmid=22150006 |pmc=3685413 |doi=10.1056/NEJMoa1109016 |url=}}</ref><ref name="pmid23086750">{{cite journal |vauthors=Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC |title=The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial |journal=Blood |volume=121 |issue=3 |pages=468–75 |date=January 2013 |pmid=23086750 |doi=10.1182/blood-2012-05-429282 |url=}}</ref><ref name="pmid22715122">{{cite journal |vauthors=Woyach JA, Johnson AJ, Byrd JC |title=The B-cell receptor signaling pathway as a therapeutic target in CLL |journal=Blood |volume=120 |issue=6 |pages=1175–84 |date=August 2012 |pmid=22715122 |doi=10.1182/blood-2012-02-362624 |url=}}</ref><ref name="pmid230867502" />
:* ''[[SF3B1]]'' [[gene]] located on [[chromosome 2]] (Poor [[prognosis]])
:* [[B cell receptor]] ([[BCR]]) [[Cell signaling|signaling]]
:* ''[[FBXW7]]'' [[gene]] located on [[chromosome 4]]
:* ''[[MYD88]]'' [[gene]] located on [[chromosome 3]]
:* ''[[TP53]]'' gene located on [[chromosome 7]]
:* ''[[NOTCH1]]'' [[gene]] located on [[chromosome 9]]<ref name="pmid230867502">{{cite journal |vauthors=Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC |title=The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial |journal=Blood |volume=121 |issue=3 |pages=468–75 |date=January 2013 |pmid=23086750 |doi=10.1182/blood-2012-05-429282 |url=}}</ref>
:* ''[[ATM]]'' [[gene]] located on [[chromosome 11]]
:* ''[[CHD2]]'' [[gene]] located on [[chromosome 15]]
:* [[MicroRNA]]
* The type of the [[genetic]] [[mutation]] is considered one of the important factors that determine the optimal management [[Protocols|protocol]] of chronic lymphocytic leukemia [[Patient|patients]].


===Microscopic Pathology===
==Microscopic Pathology==
 
* On [[microscopic]] [[histopathological]] analysis, characteristic findings of chronic lymphocytic leukemia include:
{| align="center"
:* Small [[lymphoid]] [[cell]]s
|+ '''CLL'''
:* Thin [[cytoplasmic]] border
!
:* Dense [[nucleus]]
|-valign="top"
:* Lack of [[nucleolus]]
| [[Image:CLL.jpg|thumb|CLL (more cytoplasmic space)]]
:* Clumped [[chromatin]] aggregates
| [[Image:CLL Smudge Cell.jpg|thumb|CLL Smudge Cell]]
:* The presence of smudge cells
|}
:* The presence of Gumprecht [[nuclear]] shadows
* On [[immunohistochemistry]], characteristic findings of chronic lymphocytic leukemia include:
:* [[CD5]] +ve
:* [[CD19]] +ve
:* [[CD20]] +ve
:* [[CD23]] +ve/-ve
:* [[CD38]] +ve/-ve
:* [[CD43]] +ve
:* [[Cyclin D1]] -ve
* Illustrated below is a series of microscopic images observed in chronic lymphocytic leukemia:
<gallery>
Image:
Chronic lymphocytic leukemia - low mag.jpg|Chronic lymphocytic leukemia illustrated on low magnification<ref name="patho">Chronic Lymphocytic Leukemia. Libre Pathology (2015) http://librepathology.org/wiki/index.php/B_cell_small_lymphocytic_lymphoma/chronic_lymphocytic_leukemia Accessed on October, 12 2015</ref>
Image:
Chronic lymphocytic leukemia - intermed mag.jpg|Chronic lymphocytic leukemia illustrated on intermediate magnification<ref name="patho">Chronic Lymphocytic Leukemia. Libre Pathology (2015) http://librepathology.org/wiki/index.php/B_cell_small_lymphocytic_lymphoma/chronic_lymphocytic_leukemia Accessed on October, 12 2015</ref>
Image:
Chronic lymphocytic leukemia - high mag.jpg|Chronic lymphocytic leukemia illustrated on high magnification<ref name="patho">Chronic Lymphocytic Leukemia. Libre Pathology (2015) http://librepathology.org/wiki/index.php/B_cell_small_lymphocytic_lymphoma/chronic_lymphocytic_leukemia Accessed on October, 12 2015</ref>
Image:
Chronic lymphocytic leukemia - very high mag.jpg|Chronic lymphocytic leukemia illustrated on very high magnification<ref name="patho">Chronic Lymphocytic Leukemia. Libre Pathology (2015) http://librepathology.org/wiki/index.php/B_cell_small_lymphocytic_lymphoma/chronic_lymphocytic_leukemia Accessed on October, 12 2015</ref>
</gallery>


==References==
==References==
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Latest revision as of 15:42, 28 February 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shalinder Singh, M.B.B.S.[2] Haytham Allaham, M.D. [3]

Overview

Chronic lymphocytic leukemia arises from pre-follicular, center B cells, that are normally involved in the process of human immunoglobulin production. Development of chronic lymphocytic leukemia is the result of multiple genetic mutations that promote both malignant leukemic proliferation and apoptotic resistance of mature B cells. Structural genetic mutations involved in the pathogenesis of chronic lymphocytic leukemia include chromosome 13q deletion, chromosome 17p deletion, and chromosome 11q deletion. On microscopic histopathological analysis, characteristic findings of chronic lymphocytic leukemia include small lymphoid cells, thin cytoplasmic border, lack of nucleolus, and the presence of smudge cells.


Pathogenesis

Immunology

Cytogenetics

Molecular Genetics

  • The type of the genetic mutation is considered one of the important factors that determine the optimal management protocol of chronic lymphocytic leukemia patients.

Microscopic Pathology

  • Illustrated below is a series of microscopic images observed in chronic lymphocytic leukemia:
  • Chronic lymphocytic leukemia illustrated on low magnification[21]

    Chronic lymphocytic leukemia illustrated on low magnification[21]

  • Chronic lymphocytic leukemia illustrated on intermediate magnification[21]

    Chronic lymphocytic leukemia illustrated on intermediate magnification[21]

  • Chronic lymphocytic leukemia illustrated on high magnification[21]

    Chronic lymphocytic leukemia illustrated on high magnification[21]

  • Chronic lymphocytic leukemia illustrated on very high magnification[21]

    Chronic lymphocytic leukemia illustrated on very high magnification[21]

References

  1. ↑ Herishanu Y, Katz BZ, Lipsky A, Wiestner A (April 2013). "Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications". Hematol. Oncol. Clin. North Am. 27 (2): 173–206. doi:10.1016/j.hoc.2013.01.002. PMID 23561469.
  2. ↑ Herishanu Y, Katz BZ, Lipsky A, Wiestner A (April 2013). "Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications". Hematol. Oncol. Clin. North Am. 27 (2): 173–206. doi:10.1016/j.hoc.2013.01.002. PMID 23561469.
  3. ↑ Strati P, Shanafelt TD (July 2015). "Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification". Blood. 126 (4): 454–62. doi:10.1182/blood-2015-02-585059. PMID 26065657.
  4. ↑ Ghia, P.; Caligaris-Cappio, F. (2012). "Monoclonal B-cell lymphocytosis: right track or red herring?". Blood. 119 (19): 4358–4362. doi:10.1182/blood-2012-01-404681. ISSN 0006-4971.
  5. ↑ Puente, Xose S.; Jares, Pedro; Campo, Elias (2018). "Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions". Blood. 131 (21): 2283–2296. doi:10.1182/blood-2017-10-764373. ISSN 0006-4971.
  6. ↑ Jain P, O'Brien S (December 2012). "Richter's transformation in chronic lymphocytic leukemia". Oncology (Williston Park, N.Y.). 26 (12): 1146–52. PMID 23413591.
  7. ↑ Jain P, O'Brien S (December 2012). "Richter's transformation in chronic lymphocytic leukemia". Oncology (Williston Park, N.Y.). 26 (12): 1146–52. PMID 23413591.
  8. ↑ Fournier S, Delespesse G, Rubio M, Biron G, Sarfati M (April 1992). "CD23 antigen regulation and signaling in chronic lymphocytic leukemia". J. Clin. Invest. 89 (4): 1312–21. doi:10.1172/JCI115717. PMC 442993. PMID 1532590.
  9. ↑ Geisler CH, Larsen JK, Hansen NE, Hansen MM, Christensen BE, Lund B, Nielsen H, Plesner T, Thorling K, Andersen E (October 1991). "Prognostic importance of flow cytometric immunophenotyping of 540 consecutive patients with B-cell chronic lymphocytic leukemia". Blood. 78 (7): 1795–802. PMID 1717071.
  10. ↑ Friedman DR, Guadalupe E, Volkheimer A, Moore JO, Weinberg JB (December 2018). "Clinical outcomes in chronic lymphocytic leukaemia associated with expression of CD5, a negative regulator of B-cell receptor signalling". Br. J. Haematol. 183 (5): 747–754. doi:10.1111/bjh.15632. PMID 30407619.
  11. ↑ Haerzschel A, Catusse J, Hutterer E, Paunovic M, Zirlik K, Eibel H, Krenn PW, Hartmann TN, Burger M (December 2016). "BCR and chemokine responses upon anti-IgM and anti-IgD stimulation in chronic lymphocytic leukaemia". Ann. Hematol. 95 (12): 1979–1988. doi:10.1007/s00277-016-2788-6. PMC 5093209. PMID 27542958.
  12. ↑ Döhner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M, Fischer K, Hunstein W, Lichter P (April 1997). "11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis". Blood. 89 (7): 2516–22. PMID 9116297.
  13. ↑ Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P (December 2000). "Genomic aberrations and survival in chronic lymphocytic leukemia". N. Engl. J. Med. 343 (26): 1910–6. doi:10.1056/NEJM200012283432602. PMID 11136261.
  14. ↑ Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P (December 2000). "Genomic aberrations and survival in chronic lymphocytic leukemia". N. Engl. J. Med. 343 (26): 1910–6. doi:10.1056/NEJM200012283432602. PMID 11136261.
  15. ↑ Guièze R, Robbe P, Clifford R, de Guibert S, Pereira B, Timbs A, Dilhuydy MS, Cabes M, Ysebaert L, Burns A, Nguyen-Khac F, Davi F, Véronèse L, Combes P, Le Garff-Tavernier M, Leblond V, Merle-Béral H, Alsolami R, Hamblin A, Mason J, Pettitt A, Hillmen P, Taylor J, Knight SJ, Tournilhac O, Schuh A (October 2015). "Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL". Blood. 126 (18): 2110–7. doi:10.1182/blood-2015-05-647578. PMID 26316624.
  16. ↑ Garcìa-Marco JA, Price CM, Ellis J, Morey M, Matutes E, Lens D, Colman S, Catovsky D (November 1996). "Correlation of trisomy 12 with proliferating cells by combined immunocytochemistry and fluorescence in situ hybridization in chronic lymphocytic leukemia". Leukemia. 10 (11): 1705–11. PMID 8892671.
  17. ↑ Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, Werner L, Sivachenko A, DeLuca DS, Zhang L, Zhang W, Vartanov AR, Fernandes SM, Goldstein NR, Folco EG, Cibulskis K, Tesar B, Sievers QL, Shefler E, Gabriel S, Hacohen N, Reed R, Meyerson M, Golub TR, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ (December 2011). "SF3B1 and other novel cancer genes in chronic lymphocytic leukemia". N. Engl. J. Med. 365 (26): 2497–506. doi:10.1056/NEJMoa1109016. PMC 3685413. PMID 22150006.
  18. ↑ Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC (January 2013). "The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial". Blood. 121 (3): 468–75. doi:10.1182/blood-2012-05-429282. PMID 23086750.
  19. ↑ Woyach JA, Johnson AJ, Byrd JC (August 2012). "The B-cell receptor signaling pathway as a therapeutic target in CLL". Blood. 120 (6): 1175–84. doi:10.1182/blood-2012-02-362624. PMID 22715122.
  20. ↑ 20.0 20.1 Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC (January 2013). "The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial". Blood. 121 (3): 468–75. doi:10.1182/blood-2012-05-429282. PMID 23086750.
  21. ↑ 21.0 21.1 21.2 21.3 Chronic Lymphocytic Leukemia. Libre Pathology (2015) http://librepathology.org/wiki/index.php/B_cell_small_lymphocytic_lymphoma/chronic_lymphocytic_leukemia Accessed on October, 12 2015

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