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Originally published online as doi:10.1189/jlb.0803363 on November 11, 2003

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(Journal of Leukocyte Biology. 2003;74:1139-1143.)
© 2003 by Society for Leukocyte Biology

Cyclin D2 controls B cell progenitor numbers

Azim Mohamedali*, Inês Soeiro{dagger}, Nicholas C. Lea*, Janet Glassford{dagger}, Lolita Banerji{dagger}, Ghulam J. Mufti*, Eric W.-F. Lam{dagger} and N. Shaun B. Thomas*,1

* Department of Haematological Medicine, Leukaemia Sciences, Guy’s, King’s, St. Thomas’ School of Medicine, Rayne Institute, London, United Kingdom; and
{dagger} Cancer Research–UK Labs and Section of Cancer Cell Biology, Imperial College School of Medicine at Hammersmith Hospital, London, United Kingdom

1Correspondence: Department of Haematological Medicine, Leukaemia Sciences, Guy’s, King’s, St. Thomas’ School of Medicine, Rayne Institute, 123 Coldharbour Lane, London SE5 9RS, UK. E-mail: nicholas.s.thomas{at}kcl.ac.uk


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ABSTRACT
 
Cyclin D2 affects B cell proliferation and differentiation in vivo. It is rate-limiting for B cell receptor (BCR)-dependent proliferation of B cells, and cyclin D2-/- mice lack CD5+(B1) B lymphocytes. We show here that the bone marrow (BM) of cyclin D2-/- mice contains half the numbers of Sca1+B220+ B cell progenitors but normal levels of Sca1+ progenitor cells of other lineages. In addition, clonal analysis of BM from the cyclin D2-/- and cyclin D2+/+ mice confirmed that there were fewer B cell progenitors (B220+) in the cyclin D2-/- mice. In addition, the colonies from cyclin D2-/- mice were less mature (CD19lo) than those from cyclin D2+/+ mice (CD19Hi). The number of mature B2 B cells in vivo is the same in cyclin D2-/- and cyclin D2+/+ animals. Lack of cyclin D2 protein may be compensated by cyclin D3, as cyclin-dependent kinase (cdk)6 coimmunoprecipitates with cyclin D3 but not cyclin D1 from BM mononuclear cells of cyclin D2-/- mice. It is active, as endogenous retinoblastoma protein is phosphorylated at the cdk6/4-cyclin D-specific sites, S807/811. We conclude that cyclin D2 is rate-limiting for the production of B lymphoid progenitor cells whose proliferation does not depend on BCR signaling.

Key Words: mouse • bone marrow • Sca1+ • B lymphocytes • cellular proliferation


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INTRODUCTION
 
Hematopoietic stem cells divide infrequently [1 2 3 4 ] yet are able to support the production of a huge number of mature hematopoietic cells each day. The molecular mechanisms that control entry of stem cells into the cell cycle and subsequent progenitor cell proliferation are critical for maintaining normal hematopoiesis. The retinoblastoma protein family (pRb, p130) prevents cell proliferation, and we showed previously that p130.E2F4.DP1 is the predominant complex in human quiescent CD34+ progenitor cells [5 ]. In response to mitogenic stimulus, the pRb and p130 proteins are inactivated through phosphorylation by cyclin-dependent kinases (cdk; reviewed in ref. [6 ]). This is initiated by cdk4/6-cyclin D2 and cdk4/6-cyclin D3 and is completed by cdk2-cyclin E. Inactivation of pRb and p130 allows activation of E2F-regulated genes, and cells progress from G0 through G1 into S phase (reviewed in refs. [7 , 8 ]).

We have previously studied the mechanism by which ligation of the BCR and other mitogens regulate B lymphocyte proliferation, survival, and development. Using mouse splenic B cells, we established how signals emanating from BCR regulate the pRb pathway to induce proliferation in primary, resting, mature B cells [9 10 11 ]. We have shown that genetic ablation of the cyclin D2 gene causes a depletion of the B1 (CD5+) population of B cells and a defect in immunoglobulin G (IgG) class-switching [12 ]. We also found that the existence of B2 cells in cyclin D2-/- mice was a result of compensation by cyclin D3, induced in response to signaling through the BCR [11 ]. B lymphocytes from mice null for the Rho family guanine-nucleotide exchange factor, Vav, are defective in their ability to proliferate in response to BCR cross-linking. These mice have a depletion of CD5+ (B1) lymphocytes and defective IgG class-switching. We have also demonstrated that the inability of vav-/- B cells to proliferate in response to BCR ligation was a result of lack of cyclin D2 induction [13 ]. These results collectively indicate that cyclin D2 is an essential downstream target of the BCR signaling cascade and has an important role in the proliferation, survival, and development of B cells, in particular, the CD5+ subset.

In this report, we show that the phenotype of BM from cyclin D2-/- mice contains half the numbers of Sca1+B220+ progenitors but normal levels of Sca1+ progenitor cells of other lineages. This was further confirmed with clonogenic assays with whole BM from cyclin D2+/+ and cyclin D2-/- mice, and in addition, a greater proportion of progenitor colonies from cyclin D2+/+ mice were more mature (CD19Hi). The number of mature B2 B cells in vivo was the same in cyclin D2-/- and cyclin D2+/+ animals. In addition, cdk6 coimmunoprecipitated with cyclin D3 but not cyclin D1 from BM mononuclear cells (MNC) of cyclin D2-/- mice and was active, as endogenous pRb was phosphorylated at the cdk6/4-cyclin D-specific sites, S807/811. This shows that lack of cyclin D2 was likely to be compensated by cyclin D3. We can, therefore, conclude that cyclin D2 is rate-limiting for the production of B lymphoid progenitor cells whose proliferation does not depend on BCR signaling.


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MATERIALS AND METHODS
 
Cell lines
The human B lymphoblastoid cell line Daudi was maintained in RPMI 1640/10% (v/v) fetal calf serum (FCS; Sigma Chemical Co., St. Louis, MO) and murine NIH-3T3 cells, in Dulbecco’s modified Eagle’s medium/10% (v/v) FCS (Sigma Chemical Co.).

Purification of murine Sca1+ hematopoietic progenitor cells
All cyclin D2-/- mice (C57bl/6J background) [14 ] were compared with age-matched cyclin D2+/+ littermates (3–4 months old) and were genotyped by polymerase chain reaction. BM was flushed from two femurs with Iscove’s modified Dulbecco’s medium/20% (v/v) FCS (Myoclone Super Plus)/penicillin/streptomycin (Life Sciences, Carlsbad, CA). The Sca1+ cells were bound to Sca1 MultiSort micro beads (Miltenyi Biotec, Auburn, CA) and isolated by passage through two columns (AutoMACS, Miltenyi Biotec), according to the manufacturer’s protocol. The purity was typically >95%, as determined by flow cytometry with Sca1–phycoerythrin (PE) versus isotype-control antibody (BD Biosciences, San Jose, CA).

Immunophenotyping Sca1+ cells
Cells of different lineages in the Sca1+ cell population isolated from individual mice were assayed by flow cytometry. Antibodies used were CD3e–fluorescein isothiocyanate (FITC; T cell), CD45R (B220)–FITC (B cell), CD27–PE (lymphoid), CD11b–PE (myeloid), Ly-6G–PE (myeloid), and Ter-119–PE (erythroid) and the appropriate isotype-matched controls (BD Biosciences). Gates were set using the isotype-matched controls in each case.

Colony-forming assays
BM cells from cyclin D2-/- and cyclin D2+/+ mice (12,500 and 25,000 cells) were plated in duplicate in Methocult (Stem Cells Inc., Palo Alto, CA) media containing murine stem cell factor (mSCF; 50 ng/mL; R & D Systems, Minneapolis, MN), murine fetal liver tyrosine kinase-3 ligand (mflt-3; 50 ng/mL; R & D Systems), and murine interleukin-7 (mIL-7; 10 ng/mL; R & D Systems). Pre-B and colony-forming unit (cfu)–granulocyte-erythrocyte-monocyte-megakaryocyte (GEMM) colonies were scored 8–9 days after plating. In addition, colonies were selected at random and analyzed by flow cytometry to confirm their identity. Individual colonies were harvested, washed with phosphate-buffered saline, and split into two aliquots. One aliquot was labeled with B220–FITC and CD19–PE antibodies (BD Biosciences), and the other was with the corresponding isotype controls (BD Biosciences). To compensate for the small number of cells, the antibodies were diluted 1:5 before staining. Individual colonies were analyzed by flow cytometry (FACSCaliber, BD Biosciences), and the mean fluorescent intensity (MFI) data were determined.

Immunoprecipitations and Western blotting
Immunoprecipitations were performed with 1–5 x 106 cells lysed in buffer containing 0.5% (v/v) Nonidet P-40 (see ref. [15 ]). Antibodies used were 50 µg agarose-conjugated anti-Ets1/2 (C-275 Ac) or cdk6 (C-21 Ac; Santa Cruz Biotechnology, Santa Cruz, CA). Antibodies used for Western blotting (see ref. [15 ]) recognize pRb phosphorylated at S807/811 (New England Biolabs, Beverly, MA) [16 ], pRb (PMG3245; BD-PharMingen, San Diego, CA), cyclin D1 (72-13G and HD11), cyclin D2 (M-20), cyclin D3 (18B6-10), cdk6 (C-21), and E2F-1 (C-20; Santa Cruz Biotechnology).

Statistics
A t-test of two sample populations assuming unequal variance was used to analyze statistical significance.


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RESULTS
 
Activation of cdk6/4 by cyclin D2 is clearly important for regulating the proliferation and maturation of B cells. Therefore, we wished to determine whether cyclin D2 has a role during early stages of B cell development in the BM. To this end, Sca1+ cells were isolated from the BM of cyclin D2-/- and cyclin D2+/+ mice. The proportion of these progenitor cells committed to different lineages was quantified by flow cytometric staining for CD3e (T cell [17 ]), CD45R (B220; B cell [18 ]), CD27 (lymphoid, mainly T [19 ]), CD11b (myeloid [20 ]), Ly-6G (myeloid [21 ]), and Ter-119 (erythroid [22 ]). The number of Sca1+ cells isolated from cyclin D2-/- and cyclin D2+/+ mice was the same, but cyclin D2-/- mice had half the number of Sca1+B220+ B cell progenitors. In contrast, the numbers of Sca1+ cells from other lineages were the same regardless of cyclin D2 status (Fig. 1A ). Representative flow cytometric data from one experiment are shown (of n=6 or 7), depicting the differences (P<0.0045) between the Sca1+B220+ progenitors of cyclin D2+/+ (30.6±3.6, mean±SEM) mice and the corresponding cells from the BM of cyclin D2-/- mice (14.2±3.3). In comparison, there were no observable differences in the proportions of the Sca+CD3+ or Sca+CD11b+ population in each animal (Fig. 1B) . From these data, we concluded that cyclin D2 is limiting for maintaining the correct numbers of B lymphoid progenitor cells and is not fully compensated by other mechanisms.



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  		Figure 1. The proportion of Sca1+ progenitor cells present in cyclin D2-/- and cyclin D2+/+ mice. (A) Sca1+ cells were isolated from the BM of cyclin D2-/- and cyclin D2+/+ mice. Progenitor cells of different lineages were quantified by flow cytometry using the antibodies shown (mean±SEM for n=6 or 7 individual mice). Statistical significance was judged by t-test. (B) Representative flow cytometric data from one experiment showing that cyclin D2+/+ mice have more Sca1+B220+ cells than cyclin D2-/- mice (shaded, isotype; solid, cyclin D2-/-; open, cyclin D2+/+). There were no significant differences in the proportion of Sca1+CD3+ or Sca1+CD11b+ between the groups. WT, Wild-type (cyclin D2+/+).

To confirm these results, we analyzed the BM from the cyclin D2-/- and cylclin D2+/+ mice at a clonal level. Clonal analysis of whole BM in methylcellulose medium, supplemented with cytokines supporting B cell development, showed a striking difference in the numbers and maturity of B cell colonies (B220+CD19+). The colonies were scored by morphology and verified by flow cytometric analysis of individual colonies. Cyclin D2+/+ mice had threefold more B cell colonies as compared with cyclin D2-/- mice (P<0.035), whereas there were no significant differences in the number of cfu–GEMM colonies (Fig. 2A ). In addition, B220+CD19+ colonies from cyclin D2+/+ mice had a MFI of 164 ± 21, n = 19, whereas colonies from cyclin D2-/- mice were significantly lower (MFI 91±15, n=22; P<0.0068; Fig. 2B and 2C ). Analysis of the distribution of the MFI of B220+CD19+ pre-B cell colonies showed that colonies from cyclin D2+/+ mice exhibited a higher proportion of CD19+Hi-1, whereas colonies from the cyclin D2-/- were mainly CD19+Lo-1 (Fig. 2D) . This confirms a lineage-specific role of cyclin D2 in B cell maturation.



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  		Figure 2. Clonal analysis of BM from cyclin D2+/+ and cyclin D2-/- mice. (A) BM from cyclin D2-/- and cyclin D2+/+ mice was plated in methylcellulose supplemented with mSCF, mIL-7, and mflt-3L, as described in Materials and Methods. The numbers of pre-B and cfu–GEMM colonies (n=2) were counted based on their morphology. (B) Individual colonies were randomly harvested (n=20), stained for B220 and CD19, and analyzed by flow cytometry. WT (cyclin D2+/+) mice consistently had a higher proportion of pre-B cell (B220+) colonies expressing CD19+ (MFI: 164±21) in comparison with colonies from cyclin D2-/- mice (91±15; P<0.0068). Statistical significance was judged by t-test. (C) A representative flow cytometric analysis of four colonies is shown, which highlights the difference in CD19 expression between cyclin D2+/+ and cyclin D2-/- mice. (D) The distribution of CD19 MFI for pre-B cell (B220+) colonies from cyclin D2-/- and cyclin D2+/+ from one experiment. More colonies from cyclin D2+/+ mice had a higher CD19 MFI as compared with corresponding colonies from cyclin D2-/- animals. MCF, mean cell fluorescence.

The numbers of more mature B cells (Sca1–B220+) were the same in cyclin D2-/- and cyclin D2+/+ mice. This agrees with our previous study [12 ], in which we showed that total B cell numbers as well as pre-B (B220+IgM–) and mature B (B220+IgM+) cells in the BM did not depend on cyclin D2. Thus, to determine the molecular mechanisms that compensate for lack of cyclin D2 to produce normal numbers of pre-B and mature B cells, we analyzed D-type cyclin-cdk complexes in Sca1+ and MNC from the BM of cyclin D2-/- and cyclin D2+/+ mice. Cell-cycle analysis showed that 20–30% of nucleated BM cells from cyclin D2-/- and cyclin D2+/+ animals was in S, G2/M cell-cycle phases (data not shown). Cdk6 and/or cdk4 are active in these cells, as pRb is phosphorylated at S807/811 (a cdk4/6-cyclin D-specific site) in cyclin D2-/- and cyclin D2+/+ Sca1+ progenitor cells stimulated to enter the cell cycle with cytokines in vitro (Fig. 3A ; compare days 0 and 3). Thus, another D-type cyclin must compensate for the lack of cyclin D2. Cyclin D1 is not normally present in the BM, and it is not expressed abnormally to compensate for the lack of cyclin D2, as judged by Western blotting with whole-cell lysates or cdk6 immunoprecipitations of murine BM MNC (Fig. 3B) . However, cyclin D1 was clearly detectable in the NIH-3T3 cell controls run on the same blot. We have shown that cyclin D3 compensates functionally for the lack of cyclin D2 in mature, classical B2 (CD5-ve) B lymphocytes from cyclin D2-/- mice [11 ], and so we determined whether cyclin D3 might also compensate for cyclin D2 in murine BM cells. We could not detect cyclin D3 in cyclin D2-/- or cyclin D2+/+ cells by Western blotting of whole-cell lysates, but cyclin D3 was detectable in cdk6 immunoprecipitates (Fig. 3B) . We conclude that cdk6 is activated by cyclin D3 in the absence of cyclin D2, which leads to the phosphorylation of pRb and allows the induction of E2F-regulated genes, such as E2F-1 (Fig. 3A) . As we have shown for mature B cells [11 ], such a compensatory mechanism would then allow the cells to enter the cell cycle.



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  		Figure 3. Site-specific phosphorylation of pRb in murine cyclin D2-/- Sca1+ cells. (A) pRb phosphorylated at S807/811 was analyzed in cyclin D2-/- and cyclin D2+/+ Sca1+ cells cultured with SCF, IL-3, and IL-6 for 0 and 3 days. A sample of proliferating Daudi B cells was used as a positive control. The blot was cut, and the lower half was probed for E2F-1 (h, human E2F-1; m, murine E2F-1). (B) The presence of cyclin D1 and cyclin D3 proteins coimmunoprecipitating with cdk6. Lysates of cyclin D2-/- and cyclin D2+/+ BM MNC were immunoprecipitated (Ip) with an irrelevant antibody (anti-Ets) conjugated to agarose, followed by anti-cdk6 agarose, and the presence of cyclin D1, cyclin D3, and cdk6 in each immunoprecipitate was determined by Western blotting (wb). Mouse NIH-3T3 cells were used as a positive control. Total, Total cell lysate, not immunoprecipitated (note that cdk6 is not detectable with the amount of NIH-3T3 lysate loaded).


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DISCUSSION
 
In the study presented here, we have investigated the role of cyclin D2 in regulating primary, hematopoietic progenitor cells. The functional importance of cyclin D2 is shown by the fact that cyclin D2-/- mice have half the number of Sca1+B220+ B cell progenitor cells. This suggests that the other D-type cyclin, cyclin D3, cannot fully compensate for the absence of cyclin D2 in these B cell progenitors. It is also possible that the absence of cyclin D2 expression affects only a subpopulation of B cell progenitors, which are not essential for the development of classical B2 B cells. Further work is required to determine whether rescuing cyclin D2-/- Sca1+B220+ BM cells with cyclin D3 compensates for the loss of cyclin D2 and restores normal differentiation. We have previously shown that the numbers of pre-B (B220+IgM–) and mature B (B220+IgM+) cells in the BM are the same in cyclin D2-/- and cyclin D2+/+ mice [12 ]. The data presented here show an important role for cyclin D2 in controlling the numbers of B cell precursors, but thereafter, cyclin D2 is not rate-limiting for the expansion and differentiation of these cells to immature pre-B cells. Analagous roles in hematopoietic development have been described for other cell-cycle regulators, including p21Cip1 and p27Kip1. In the p21Cip1-/- mice, stem-cell number was doubled, but the progenitor populations remained unchanged [23 ], and the p27Kip1-/- mice have normal stem-cell pool but increased progenitor populations [24 ]. In both cases, the number of mature cells in peripheral blood was normal, implying that compensation for the functions of p21Cip1 and p27Kip1, respectively, had taken place during maturation of each hematopoietic lineage. Cell type-specific roles and functional compensation by each of the three D-type cyclins during mouse development were shown in mice only expressing one of the three cyclins. The single cyclin expressed sufficed in most cell types, except that cyclin D1-only mice developed megaloblastic anemia, cyclin D2-only had neurological abnormalities, and cyclin D3-only lacked normal cerebella [25 ]. Cell type-specific roles for cell-cycle regulatory proteins have also been demonstrated in human cells. Furukawa et al. [26 ] showed that there was selective up-regulation of cyclin D3 in megakaryocytes derived from CD34+ cells and that blocking the induction of cyclin D3 prevented megakaryocyte differentiation.

The functional role of cyclin D2 in the proliferation and development of BCR-containing B cells has previously been documented [11 12 13 , 27 , 28 ]. In the current study, we have shown that cyclin D2 has an important role in development of B cell progenitors, whose proliferation does not depend on BCR-derived signals. We demonstrated previously that CD5+ B1 cells are dependent on cyclin D2, whereas Sca1+B220+ progenitors and mature B2 cells can compensate by inducing cyclin D3. It is, however, unclear whether this decrease in B cell progenitors in cyclin D2-/- mice has any causative relationship with the decrease in CD5 +ve B1 B cells observed in the same knockouts. The cells in B cell chronic lymphocytic leukemia (CLL) are CD5 +ve, and they are perceived as the malignant counterpart of normal CD5 +ve B1 B cells. Our data are therefore of potential therapeutic importance, as selective inhibitors of cyclin D2-dependent cdk activity would be expected to preferentially target the expansion of malignant B1 cells in patients with B cell CLL.


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ACKNOWLEDGEMENTS
 
This work was supported by the Charles Wolfson Charitable Trust (N. S. B. T., A. M., and N. C. L.), Leukaemia Research Fund (N. S. B. T., E. W-F. L., and J. G.), and Cancer Research–UK (E. W-F. L.). I. S. is supported by a Ph.D. studentship from Fundação para a Ciência e a Tecnologia, Portugal. A University of London Trust Postgraduate Studentship supported L. B. We thank Piotr Sicinski for making the cyclin D2-/- mice available, Nigel Westwood for help in isolating Sca1-positive cells, and Stephen Devereux and our colleagues in Leukaemia Sciences for critical comments on the manuscript.

Received August 1, 2003; revised August 22, 2003; accepted September 9, 2003.


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