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• W1964228724 abstract "We report here that in chronic lymphocytic leukemia (CLL), the propensity to generate clonal B cells has been acquired already at the hematopoietic stem cell (HSC) stage. HSCs purified from patients with CLL displayed lymphoid-lineage gene priming and produced a high number of polyclonal B cell progenitors. Strikingly, their maturation into B cells was restricted always to mono- or oligo-clones with CLL-like phenotype in xenogeneic recipients. These B cell clones were independent of the original CLL clones because they had their own immunoglobulin VDJ genes. Furthermore, they used preferentially VH genes frequently used in human CLL, presumably reflecting the role of B cell receptor signaling in clonal selection. These data suggest that HSCs can be involved in leukemogenesis even in mature lymphoid tumors. We report here that in chronic lymphocytic leukemia (CLL), the propensity to generate clonal B cells has been acquired already at the hematopoietic stem cell (HSC) stage. HSCs purified from patients with CLL displayed lymphoid-lineage gene priming and produced a high number of polyclonal B cell progenitors. Strikingly, their maturation into B cells was restricted always to mono- or oligo-clones with CLL-like phenotype in xenogeneic recipients. These B cell clones were independent of the original CLL clones because they had their own immunoglobulin VDJ genes. Furthermore, they used preferentially VH genes frequently used in human CLL, presumably reflecting the role of B cell receptor signaling in clonal selection. These data suggest that HSCs can be involved in leukemogenesis even in mature lymphoid tumors. HSCs in CLL have cell-intrinsic propensity to generate clonal CLL-like B cells Abnormal karyotypes are not required for appearance of such B cell clones The majority of single HSCs in patients with CLL display lymphoid-lineage priming HSCs can be involved in oncogenesis even in mature lymphoid tumors HSCs capable of self-renewal should be the main target for accumulating mutational events to develop hematological malignancies. This paper shows that HSCs play such a role also in mature lymphoid malignancies. Most human CLL cases have a precursor phase, called monoclonal B lymphocytosis (MBL), that is asymptomatic monoclonal or oligoclonal proliferation of B cells. HSCs from patients with CLL but not normal HSCs developed monoclonal or oligoclonal B cells simulating MBL after xenogeneic transplantation. Acquisition of chromosomal abnormalities appeared to be secondary events to transform MBL into clinical CLL. Thus, even in CLL, accumulation of oncogenic events starts at the HSC stage. Our xenograft model might be very useful to understand the pathogenesis of human CLL. Malignant transformation can occur through a multistep acquisition of critical somatic mutations. Therefore, the precursor of malignant stem cells should have a long life span to accumulate such mutations. In human hematopoiesis, genetic abnormalities for transformation should be accumulated in self-renewing hematopoietic stem cells (HSCs). HSCs can continuously produce a number of progenitors with the same genetic alteration, which are also potential targets for additional mutations (Rossi et al., 2008Rossi D.J. Jamieson C.H. Weissman I.L. Stems cells and the pathways to aging and cancer.Cell. 2008; 132: 681-696Abstract Full Text Full Text PDF PubMed Scopus (704) Google Scholar). Such HSCs or downstream progenitors finally become leukemia stem cells that possess self-renewal but lack normal differentiation activity (Huntly et al., 2004Huntly B.J. Shigematsu H. Deguchi K. Lee B.H. Mizuno S. Duclos N. Rowan R. Amaral S. Curley D. Williams I.R. et al.MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors.Cancer Cell. 2004; 6: 587-596Abstract Full Text Full Text PDF PubMed Scopus (586) Google Scholar, So et al., 2003So C.W. Karsunky H. Passegué E. Cozzio A. Weissman I.L. Cleary M.L. MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice.Cancer Cell. 2003; 3: 161-171Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). This notion of leukemia development has been well accepted to explain acute myeloid leukemia (AML) development, and AML-initiating cells capable of reconstituting human leukemias in xenogeneic hosts have been purified (Bonnet and Dick, 1997Bonnet D. Dick J.E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.Nat. Med. 1997; 3: 730-737Crossref PubMed Scopus (5477) Google Scholar) as a potential therapeutic target (Jin et al., 2006Jin L. Hope K.J. Zhai Q. Smadja-Joffe F. Dick J.E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells.Nat. Med. 2006; 12: 1167-1174Crossref PubMed Scopus (1001) Google Scholar, Jin et al., 2009Jin L. Lee E.M. Ramshaw H.S. Busfield S.J. Peoppl A.G. Wilkinson L. Guthridge M.A. Thomas D. Barry E.F. Boyd A. et al.Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells.Cell Stem Cell. 2009; 5: 31-42Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar, Kikushige et al., 2010Kikushige Y. Shima T. Takayanagi S. Urata S. Miyamoto T. Iwasaki H. Takenaka K. Teshima T. Tanaka T. Inagaki Y. Akashi K. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells.Cell Stem Cell. 2010; 7: 708-717Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar, Majeti et al., 2009Majeti R. Chao M.P. Alizadeh A.A. Pang W.W. Jaiswal S. Gibbs Jr., K.D. van Rooijen N. Weissman I.L. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells.Cell. 2009; 138: 286-299Abstract Full Text Full Text PDF PubMed Scopus (1110) Google Scholar, Saito et al., 2010Saito Y. Kitamura H. Hijikata A. Tomizawa-Murasawa M. Tanaka S. Takagi S. Uchida N. Suzuki N. Sone A. Najima Y. et al.Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells.Sci. Transl. Med. 2010; 2: 17ra19Crossref Scopus (317) Google Scholar). However, in lymphoid malignancies, leukemia or lymphoma cells usually have monoclonal immunoglobulin or T cell receptor gene rearrangements, suggesting that lymphoid malignant stem cells originate after cells have committed to the lymphoid lineage. Recent studies have shown that acute lymphoid leukemia (ALL)-initiating cells upon xenogeneic transplantation are composed of multiple genetically distinct subclones (Anderson et al., 2011Anderson K. Lutz C. van Delft F.W. Bateman C.M. Guo Y. Colman S.M. Kempski H. Moorman A.V. Titley I. Swansbury J. et al.Genetic variegation of clonal architecture and propagating cells in leukaemia.Nature. 2011; 469: 356-361Crossref PubMed Scopus (645) Google Scholar, Notta et al., 2011Notta F. Mullighan C.G. Wang J.C. Poeppl A. Doulatov S. Phillips L.A. Ma J. Minden M.D. Downing J.R. Dick J.E. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells.Nature. 2011; 469: 362-367Crossref PubMed Scopus (389) Google Scholar). These data clearly show that lymphoid cells can easily accumulate genetic abnormalities, presumably because they can persist longer than myeloid cells, and are capable of clonal expansion simulating self-renewal (Luckey et al., 2006Luckey C.J. Bhattacharya D. Goldrath A.W. Weissman I.L. Benoist C. Mathis D. Memory T and memory B cells share a transcriptional program of self-renewal with long-term hematopoietic stem cells.Proc. Natl. Acad. Sci. USA. 2006; 103: 3304-3309Crossref PubMed Scopus (208) Google Scholar). Because of such property of lymphoid cells, the involvement of HSCs in lymphoid leukemogenesis has never been underscored. Chronic lymphocytic leukemia (CLL), the most common leukemia in adults in western countries, is a mature B cell malignancy (Chiorazzi et al., 2005Chiorazzi N. Rai K.R. Ferrarini M. Chronic lymphocytic leukemia.N. Engl. J. Med. 2005; 352: 804-815Crossref PubMed Scopus (1326) Google Scholar). It is characterized by accumulation of clonal B cells in the blood, the bone marrow, and the lymphoid tissues. The consistent clonal expansion of mature B cells frequently expressing CD5 is the major phenotype of patients with CLL. Unfortunately, the development of its xenograft models by transplanting primary CLL cells into immunodeficient hosts has failed because the engraftment was extremely inefficient (Dürig et al., 2007Dürig J. Ebeling P. Grabellus F. Sorg U.R. Möllmann M. Schütt P. Göthert J. Sellmann L. Seeber S. Flasshove M. et al.A novel nonobese diabetic/severe combined immunodeficient xenograft model for chronic lymphocytic leukemia reflects important clinical characteristics of the disease.Cancer Res. 2007; 67: 8653-8661Crossref PubMed Scopus (57) Google Scholar, Hummel et al., 1996Hummel J.L. Lichty B.D. Reis M. Dubé I. Kamel-Reid S. Engraftment of human chronic lymphocytic leukemia cells in SCID mice: in vivo and in vitro studies.Leukemia. 1996; 10: 1370-1376PubMed Google Scholar). Thus, the search for CLL-initiating cells has never been successful. Human CLL cells have functional B cell receptors (BCRs) on their surface as a result of productive rearrangement of immunoglobulin genes (Caligaris-Cappio and Ghia, 2008Caligaris-Cappio F. Ghia P. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease?.J. Clin. Oncol. 2008; 26: 4497-4503Crossref PubMed Scopus (166) Google Scholar, Chiorazzi et al., 2005Chiorazzi N. Rai K.R. Ferrarini M. Chronic lymphocytic leukemia.N. Engl. J. Med. 2005; 352: 804-815Crossref PubMed Scopus (1326) Google Scholar, Stevenson and Caligaris-Cappio, 2004Stevenson F.K. Caligaris-Cappio F. Chronic lymphocytic leukemia: revelations from the B-cell receptor.Blood. 2004; 103: 4389-4395Crossref PubMed Scopus (332) Google Scholar). CLL has been divided into two subgroups based on the presence of somatic hypermutations within the variable regions of immunoglobulin heavy-chain (IGHV) genes, which normally occurs in the germinal center during naive to memory B cell transition. The group of CLLs with mutated BCRs has a more favorable prognosis than those with unmutated BCRs (Hamblin et al., 1999Hamblin T.J. Davis Z. Gardiner A. Oscier D.G. Stevenson F.K. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia.Blood. 1999; 94: 1848-1854PubMed Google Scholar). However, recent studies suggest that both types of CLLs originate from self-reactive B cell precursors and that the status of somatic hypermutations does not indicate their origin (Hervé et al., 2005Hervé M. Xu K. Ng Y.S. Wardemann H. Albesiano E. Messmer B.T. Chiorazzi N. Meffre E. Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity.J. Clin. Invest. 2005; 115: 1636-1643Crossref PubMed Scopus (261) Google Scholar, Klein et al., 2001Klein U. Tu Y. Stolovitzky G.A. Mattioli M. Cattoretti G. Husson H. Freedman A. Inghirami G. Cro L. Baldini L. et al.Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells.J. Exp. Med. 2001; 194: 1625-1638Crossref PubMed Scopus (781) Google Scholar, Rosenwald et al., 2001Rosenwald A. Alizadeh A.A. Widhopf G. Simon R. Davis R.E. Yu X. Yang L. Pickeral O.K. Rassenti L.Z. Powell J. et al.Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia.J. Exp. Med. 2001; 194: 1639-1647Crossref PubMed Scopus (928) Google Scholar). Interestingly, CLL cells preferentially use the IGHV genes, such as VH1, VH3, and VH4 regions (Chiorazzi and Ferrarini, 2003Chiorazzi N. Ferrarini M. B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor.Annu. Rev. Immunol. 2003; 21: 841-894Crossref PubMed Scopus (308) Google Scholar, Fais et al., 1998Fais F. Ghiotto F. Hashimoto S. Sellars B. Valetto A. Allen S.L. Schulman P. Vinciguerra V.P. Rai K. Rassenti L.Z. et al.Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors.J. Clin. Invest. 1998; 102: 1515-1525Crossref PubMed Scopus (732) Google Scholar), and express a restricted BCR repertoire including antibodies with quasi-identical complementarity-determining region 3 (CDR3) (Ghiotto et al., 2004Ghiotto F. Fais F. Valetto A. Albesiano E. Hashimoto S. Dono M. Ikematsu H. Allen S.L. Kolitz J. Rai K.R. et al.Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia.J. Clin. Invest. 2004; 113: 1008-1016Crossref PubMed Scopus (190) Google Scholar, Messmer et al., 2004Messmer B.T. Albesiano E. Efremov D.G. Ghiotto F. Allen S.L. Kolitz J. Foa R. Damle R.N. Fais F. Messmer D. et al.Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia.J. Exp. Med. 2004; 200: 519-525Crossref PubMed Scopus (344) Google Scholar, Tobin et al., 2003Tobin G. Thunberg U. Johnson A. Eriksson I. Söderberg O. Karlsson K. Merup M. Juliusson G. Vilpo J. Enblad G. et al.Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted Vlambda2-14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope.Blood. 2003; 101: 4952-4957Crossref PubMed Scopus (263) Google Scholar, Tobin et al., 2004Tobin G. Thunberg U. Karlsson K. Murray F. Laurell A. Willander K. Enblad G. Merup M. Vilpo J. Juliusson G. et al.Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia.Blood. 2004; 104: 2879-2885Crossref PubMed Scopus (225) Google Scholar, Widhopf et al., 2004Widhopf 2nd, G.F. Rassenti L.Z. Toy T.L. Gribben J.G. Wierda W.G. Kipps T.J. Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins.Blood. 2004; 104: 2499-2504Crossref PubMed Scopus (200) Google Scholar), suggesting specific antigen recognition by CLL cells (Chiorazzi and Ferrarini, 2003Chiorazzi N. Ferrarini M. B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor.Annu. Rev. Immunol. 2003; 21: 841-894Crossref PubMed Scopus (308) Google Scholar, Stevenson and Caligaris-Cappio, 2004Stevenson F.K. Caligaris-Cappio F. Chronic lymphocytic leukemia: revelations from the B-cell receptor.Blood. 2004; 103: 4389-4395Crossref PubMed Scopus (332) Google Scholar). To trace the origin of genetic aberration in human CLL, it is important to note the fact that CLL cells are not always monoclonal, but more than one CLL clone is found in up to ∼14% of patients with CLL (Sanchez et al., 2003Sanchez M.L. Almeida J. Gonzalez D. Gonzalez M. Garcia-Marcos M.A. Balanzategui A. Lopez-Berges M.C. Nomdedeu J. Vallespi T. Barbon M. et al.Incidence and clinicobiologic characteristics of leukemic B-cell chronic lymphoproliferative disorders with more than one B-cell clone.Blood. 2003; 102: 2994-3002Crossref PubMed Scopus (95) Google Scholar). Furthermore, a recent cohort study has shown that 44 out of 45 patients with CLL have a precursor state such as monoclonal B lymphocytosis (MBL) for 6 months to 7 years (Landgren et al., 2009Landgren O. Albitar M. Ma W. Abbasi F. Hayes R.B. Ghia P. Marti G.E. Caporaso N.E. B-cell clones as early markers for chronic lymphocytic leukemia.N. Engl. J. Med. 2009; 360: 659-667Crossref PubMed Scopus (279) Google Scholar). MBL represents asymptomatic proliferation of clonal B cells whose numbers in circulation are below 5000/μl (Marti et al., 2005Marti G.E. Rawstron A.C. Ghia P. Hillmen P. Houlston R.S. Kay N. Schleinitz T.A. Caporaso N. International Familial CLL ConsortiumDiagnostic criteria for monoclonal B-cell lymphocytosis.Br. J. Haematol. 2005; 130: 325-332Crossref PubMed Scopus (331) Google Scholar). Of note, human MBL is frequently (20%–70% of total cases) composed of more than one B cell clone (Dagklis et al., 2009Dagklis A. Fazi C. Sala C. Cantarelli V. Scielzo C. Massacane R. Toniolo D. Caligaris-Cappio F. Stamatopoulos K. Ghia P. The immunoglobulin gene repertoire of low-count chronic lymphocytic leukemia (CLL)-like monoclonal B lymphocytosis is different from CLL: diagnostic implications for clinical monitoring.Blood. 2009; 114: 26-32Crossref PubMed Scopus (110) Google Scholar, Lanasa et al., 2010Lanasa M.C. Allgood S.D. Volkheimer A.D. Gockerman J.P. Whitesides J.F. Goodman B.K. Moore J.O. Weinberg J.B. Levesque M.C. Single-cell analysis reveals oligoclonality among ‘low-count’ monoclonal B-cell lymphocytosis.Leukemia. 2010; 24: 133-140Crossref PubMed Scopus (53) Google Scholar, Nieto et al., 2009Nieto W.G. Almeida J. Romero A. Teodosio C. Lopez A. Henriques A.F. Sanchez M.L. Jara-Acevedo M. Rasillo A. Gonzalez M. et al.Increased frequency (12%) of circulating CLL-like B-cell clones in healthy individuals using a high-sensitive multicolor flow cytometry approach.Blood. 2009; 114: 33-37Crossref PubMed Scopus (170) Google Scholar). More than a half of such MBL clones express CD5 (Scarfò et al., 2010Scarfò L. Dagklis A. Scielzo C. Fazi C. Ghia P. CLL-like monoclonal B-cell lymphocytosis: are we all bound to have it?.Semin. Cancer Biol. 2010; 20: 384-390Crossref PubMed Scopus (43) Google Scholar), and patients with these CLL-like MBL clones frequently develop into clinical CLL (Rawstron et al., 2008Rawstron A.C. Bennett F.L. O'Connor S.J. Kwok M. Fenton J.A. Plummer M. de Tute R. Owen R.G. Richards S.J. Jack A.S. Hillmen P. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.N. Engl. J. Med. 2008; 359: 575-583Crossref PubMed Scopus (460) Google Scholar). Furthermore, like CLL cells, CD5+ MBL clones use a biased set of VH genes, including VH1, 3, and 4 (Rawstron et al., 2008Rawstron A.C. Bennett F.L. O'Connor S.J. Kwok M. Fenton J.A. Plummer M. de Tute R. Owen R.G. Richards S.J. Jack A.S. Hillmen P. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.N. Engl. J. Med. 2008; 359: 575-583Crossref PubMed Scopus (460) Google Scholar). The usage of such biased BCR types found in CLL and its precedent MBL clones strongly suggests that the antigenic drive contributes to clonal expansion and/or cell survival also during the transition from MBL to clinical CLL (Pleyer et al., 2009Pleyer L. Egle A. Hartmann T.N. Greil R. Molecular and cellular mechanisms of CLL: novel therapeutic approaches.Nat. Rev. Clin. Oncol. 2009; 6: 405-418Crossref PubMed Scopus (126) Google Scholar). The question is: If progression from MBL to CLL reflects stepwise leukemogenesis, at what stage does the first oncogenic event occur. The existence of oligoclonal B cell clones in patients with CLL and with those MBL strongly suggests that the first oncogenic event could at least be traced up to the progenitor or HSCs that have not rearranged IGH genes. These data led us to search for CLL-initiating cells within the early hematopoietic stages utilizing an efficient xenotransplantation system. To search for the cell population with CLL-initiating activity in human CLL, we first tried to locate the developmental stage at which CLL B cell clones appear. Patients' characteristics are shown in Table S1 available online. Figure 1A shows the FACS analysis of the bone marrow of a patient with CLL. The bone marrow contained CD34+CD38− HSCs (Bhatia et al., 1997Bhatia M. Wang J.C. Kapp U. Bonnet D. Dick J.E. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice.Proc. Natl. Acad. Sci. USA. 1997; 94: 5320-5325Crossref PubMed Scopus (723) Google Scholar), and the CD34+CD38+ progenitor fraction that contains myeloid and lymphoid progenitors (Manz et al., 2002Manz M.G. Miyamoto T. Akashi K. Weissman I.L. Prospective isolation of human clonogenic common myeloid progenitors.Proc. Natl. Acad. Sci. USA. 2002; 99: 11872-11877Crossref PubMed Scopus (395) Google Scholar). Interestingly, percentages of CD10+CD19+ proB cells in the bone marrow of patients with CLL were high in most patients: in 12 out of 13 patients with CLL, proB cell frequency was higher than the average of 7 normal controls, and the average proB cell frequency in patients with CLL was higher than that in normal controls by ∼5-fold (Figure 1B). In contrast, frequencies of the CD34+CD38− HSC population were equal (Figure 1B). Recent reports have shown that the CD34+CD38− HSC population can further be divided into subpopulations including CD90+CD45RA−, CD90−CD45RA−, and CD90−CD45RA+ that mainly contain long-term HSCs (LT-HSCs), multipotent progenitors (Majeti et al., 2007Majeti R. Park C.Y. Weissman I.L. Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood.Cell Stem Cell. 2007; 1: 635-645Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar), and early lymphoid/myeloid progenitors (Doulatov et al., 2010Doulatov S. Notta F. Eppert K. Nguyen L.T. Ohashi P.S. Dick J.E. Revised map of the human progenitor hierarchy shows the origin of macrophages and dendritic cells in early lymphoid development.Nat. Immunol. 2010; 11: 585-593Crossref PubMed Scopus (358) Google Scholar, Goardon et al., 2011Goardon N. Marchi E. Atzberger A. Quek L. Schuh A. Soneji S. Woll P. Mead A. Alford K.A. Rout R. et al.Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia.Cancer Cell. 2011; 19: 138-152Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar), respectively. We performed the HSC subpopulation analysis in six CLL cases, and found that the distribution of these HSC subpopulations did not differ in normal and CLL bone marrow, and the majority (∼60%) of CD34+CD38− cells were the most primitive CD90+CD45RA− population (Figure 1B). Thus, we tested whether the expansion at the proB stage reflects clonal proliferation of CLL precursors by analyzing the rearrangement status of the IGH gene. As shown in Figure 1C, the purified CD34+CD38− HSC population in patients with CLL (CLL-HSCs) presented the germline configuration, and CD34−CD19+ CLL cells had a clonal IGH rearrangement. Of note, proB cells in CLL bone marrow exhibited polyclonal rearrangement of IGH genes, suggesting that CLL clones are selected in vivo among such expanded polyclonal B cells. These data clearly show that CD34+CD38− CLL-HSC populations do not rearrange the IGH gene, and therefore, are not contaminated with detectable CLL clones. However, CLL-HSCs are able to develop a higher number of polyclonal B cells as compared to normal HSCs, suggesting that developmental potential of CLL-HSCs is skewed toward B cell lineage probably reflecting their cell-intrinsic abnormality. We then tried to identify the CLL-initiating cell population by transplanting subpopulations of CLL cells into immunodeficient mice. In these experiments, NOD/SCID/IL2rgnull (NSG) (Ishikawa et al., 2005Ishikawa F. Yasukawa M. Lyons B. Yoshida S. Miyamoto T. Yoshimoto G. Watanabe T. Akashi K. Shultz L.D. Harada M. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor gamma chain(null) mice.Blood. 2005; 106: 1565-1573Crossref PubMed Scopus (713) Google Scholar) newborns or NOD/RAG-1−/−IL2rgnull (NRG) (Pearson et al., 2008Pearson T. Shultz L.D. Miller D. King M. Laning J. Fodor W. Cuthbert A. Burzenski L. Gott B. Lyons B. et al.Non-obese diabetic-recombination activating gene-1 (NOD-Rag1 null) interleukin (IL)-2 receptor common gamma chain (IL2r gamma null) null mice: a radioresistant model for human lymphohaematopoietic engraftment.Clin. Exp. Immunol. 2008; 154: 270-284Crossref PubMed Scopus (148) Google Scholar) adult mice were used as recipients (Table 1).Table 1Results of Xenogeneic Transplantation Assays of CLL-HSCsPatient No.MouseWeeks after TransplantTransplanted CellsNo. of Cells Transplanted(×103 cells)hCD45+ Cells (%)hCD19+ in hCD45+ (%)hCD33+ in hCD45+ (%)CD5− B CellCD5+ B CellCells in Total B Cells (%)No. of ClonesCells in Total B Cells (%)No. of Clones11-1NRG16CD34+CD38−200.157.9NA1001––1-2NRG18CD34+CD38−400.532.652.893.6P6.4322NRG12CD34+CD38−650.133.3NA1001––33NRG16CD34+CD38−141.692.3NA1001––44NSG5CD34+CD38−3.322.45.1440.41002––55NSG11CD34+CD38−7.611.4837.189.2210.8266NSG12CD34+CD38−7.018.77.54891002––77-1NSG24CD34+CD38−3031.653.232.595.0P5.037-2NSG24CD34+CD38−7.01.817.658.165.7234.327-3NSG24CD34+CD38−164.363.331.389.8P10.2288NSG24CD34+CD38−184.117.560.289111399-1NSG13CD34+CD38−4.02.072.319.497.5P2.419-2NSG13CD34+CD38−5.014.010.251.81001––1010-1NSG13CD34+CD38−1518.188.32.91001––10-2NSG13CD34+CD38−1011.068.520.11001––10-3NSG30CD34+CD38−5.018.563.324.196.933.111111-1NSG33CD34+CD38−100.550.1NA1001––11-2NRG14CD34+CD38−180.128.6501002––1212NRG12CD34+CD38−CD90+6.00.147.531.989.6P10.421313-1NRG14CD34+CD38−CD90+8.00.587.12.594.7P5.3113-2NRG14CD34+CD38−CD90+8.03.788.11.196P3.9113-3NRG17CD34+CD38−CD90+6.01.086.15.299P1.021414NRG9CD34+CD38−601.075.117.19920.921515NRG9CD34+CD38−CD90+100.267.7261001––1616NRG21CD34+CD38−CD90+5.01.892.11.998P1.71NA, not analyzed; P, polyclonal. Open table in a new tab NA, not analyzed; P, polyclonal. CD19+ CLL cells were purified from the blood or the bone marrow of patients 1–8, and 0.2 to 1 × 107 cells were transplanted. However, even until 6 months after transplantation, human CD45+ cells were never found in any of the 15 recipients analyzed (Figure S1). These data strongly suggest that CLL cells are incompetent for expansion to recapitulate human CLL in immunodeficient mice. We also transplanted 104 CD34+CD38+CD10+CD19+ proB cells in these patients, but none of ten recipients was engrafted 12 weeks after transplantation (not shown). These data led us to analyze the engraftment potential of CLL-HSCs in the xenogeneic transplantation system. Purified 3.3 × 103 to 6.5 × 104 CD34+CD38− HSCs or 5.0 × 103 to 1 × 104 CD34+CD38−CD90+ LT-HSCs from 16 independent patients with CLL were transplanted into 25 mice (Table 1; Table S2), and ∼104 CD34+CD38− cells from 11 normal controls were transplanted into 29 mice. Previous xenogeneic transplantation studies have shown that normal HSCs are able to reconstitute multilineage hematopoietic cells, and polyclonal B cells are normally developed in NOD-SCID or NSG mouse bone marrow and spleen (Hiramatsu et al., 2003Hiramatsu H. Nishikomori R. Heike T. Ito M. Kobayashi K. Katamura K. Nakahata T. Complete reconstitution of human lymphocytes from cord blood CD34+ cells using the NOD/SCID/gammacnull mice model.Blood. 2003; 102: 873-880Crossref PubMed Scopus (219) Google Scholar, Ishikawa et al., 2005Ishikawa F. Yasukawa M. Lyons B. Yoshida S. Miyamoto T. Yoshimoto G. Watanabe T. Akashi K. Shultz L.D. Harada M. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor gamma chain(null) mice.Blood. 2005; 106: 1565-1573Crossref PubMed Scopus (713) Google Scholar, Kolar et al., 2004Kolar G.R. Yokota T. Rossi M.I. Nath S.K. Capra J.D. Human fetal, cord blood, and adult lymphocyte progenitors have similar potential for generating B cells with a diverse immunoglobulin repertoire.Blood. 2004; 104: 2981-2987Crossref PubMed Scopus (20) Google Scholar, Matsumura et al., 2003Matsumura T. Kametani Y. Ando K. Hirano Y. Katano I. Ito R. Shiina M. Tsukamoto H. Saito Y. Tokuda Y. et al.Functional CD5+ B cells develop predominantly in the spleen of NOD/SCID/gammac(null) (NOG) mice transplanted either with human umbilical cord blood, bone marrow, or mobilized peripheral blood CD34+ cells.Exp. Hematol. 2003; 31: 789-797Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, Rossi et al., 2001Rossi M.I. Medina K.L. Garrett K. Kolar G. Comp P.C. Shultz L.D. Capra J.D. Wilson P. Schipul A. Kincade P.W. Relatively normal human lymphopoiesis but rapid turnover of newly formed B cells in transplanted nonobese diabetic/SCID mice.J. Immunol. 2001; 167: 3033-3042PubMed Google Scholar). As shown in Figures 2A and 2B , both CLL-HSCs and normal HSCs gave rise to secondary CD34+CD38− HSCs, CD34+CD38+ progenitor cells, CD34−CD19+ B cells, and CD34−CD33+ myeloid cells in the bone marrow. Of note, the percentage of CLL-HSC-derived human proB cells was significantly higher than that of normal HSC-derived ones (Figure 2C), as we found in the bone marrow analysis of patients with CLL and normal controls (Figure 1B), suggesting again that differentiation of CLL-HSCs skews toward B cell lineage. Interestingly, CLL-HSC-derived CD19+ B cells in the bone marrow frequently coexpressed CD5 (Figure 3B and Table 1), which is a characteristic of de novo human CLL cells. Normal human HSCs generated mainly CD5− and very rare (<1%) CD5+ B cells in the bone marrow in all 29 recipients. In total, 5 out of 25 mice transplanted with CLL-HSCs developed both CD5+ and CD5− B cell clones, 9 mice developed only CD5+ B cell clones, and the remaining 11 mice developed only CD5− B cell clones (Table 1). These CD5+ B cells derived from CLL-HSCs expressed surface IgM, CD20, and CD23 (Figure 3C) but lacked CD10, like original CLL cells in patients.Figure 3CLL-HSCs Give Rise to Monoclonal or Oligoclonal B Cells with CLL-like Phenotype after Xenogeneic TransplantationShow full caption(A) FACS and IGH rearrangement analysis of mice transplanted with normal HSCs. CD5+ B cells were rare, and both CD5+CD19+ and CD5−CD19+ B cell fractions displayed polyclonal IGH rearrangement.(B) FACS and IGH rearrangement analysis of mice transplanted with CLL-HSCs. Development of CD5+CD19+ B cells was frequently seen in these mice (as summarized in Table 1). In mouse 13-1, CD5− B cells were polyclonal, but CD5+ B cells were monoclonal. In other mice shown here, both CD5− and CD5+ B cells are composed of one to three B cell clones. The B cell clones developed in mice always had VDJ genes different from those of the ori" @default.
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• W1964228724 title "Self-Renewing Hematopoietic Stem Cell Is the Primary Target in Pathogenesis of Human Chronic Lymphocytic Leukemia" @default.
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