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IntroductionB lymphocyte development in the bone marrow features a sequential rearrangement of the heavy and light chain loci and a transient expression of pre-B-cell receptor (pre-BCR). After a productive immunoglobulin heavy chain rearrangement at the pro-B stage, heavy chain protein mu pairs with the surrogate light chain (SLC) 5 and Vpre-B. Together with the signaling molecules Ig␣ and Ig␤, they form the pre-BCR on the cell surface. 1 The activation of the pre-BCR is cell autonomous and independent of ligand binding. 2 Signal emanated from the pre-BCR stimulates pre-B-cell proliferation and the formation of so-called large, cycling pre-B cells. After a limited number of cell divisions, cycling pre-B cells exit the cell cycle and become small, resting pre-B cells. Light chain rearrangement and transcription takes place primarily in those quiescent pre-B cells. Pre-BCR-induced B-cell self-propagation is an important event in B-cell development through which pre-B cells expressing successfully rearranged heavy chains are clonally expanded prior to light chain rearrangement. 3 In addition, pre-BCR signaling is also important for inhibiting the expression of Rag1 and Rag2, thus facilitating the maintenance of allelic exclusion of the heavy chain locus. 4 Moreover, pre-BCR signaling increases the accessibility of the light chain loci, thereby promoting light chain rearrangement and transcription. 5 The initial burst of cell proliferation at the large pre-B-cell stage and the subsequent passage into the quiescent, small pre-Bcell stage are critical events in pre-B-cell development. Disruption of the transition from large, cycling pre-B cells to small, resting pre-B cells often leads to a block in pre-B-cell development. [6][7][8] However, the molecular mechanisms that control pre-B-cell expansion, and therefore, the transition from cycling pre-B to resting pre-B cells, are still not clear. It has been shown that the pre-BCR is only expressed on cycling pre-B cells but not on small, resting pre-B cells. 9 Thus, down-regulation of pre-BCR has been linked to cessation of cell proliferation and cell-cycle withdrawal. 3,10 Ikaros and Aiolos are members of the Ikaros family of transcription factors. 11 The Ikaros family transcription factors interact with each other and other members of the Ikaros family. The N-terminal domain of Ikaros family proteins is responsible for DNA binding, whereas the C-terminal domain is involved in dimerization. The formation of Ikaros homo-and heterodimers through the C-terminal dimerization domain increases their affinity for DNA. 12,13 It has been demonstrated that expression of Ikaros and Aiolos are increased in pre-B cells relative to pro-B cells, suggesting that Ikaros and Aiolos may play an important role in pre-B-cell development. 14 Indeed, Aiolos has been shown to be directly involved in the silencing of the 5 gene in pre-B cells. 15 It has been reported that pre-BCR signaling induces the expression of Aiolos, which in turn, competes with EBF, an essential transcriptional activator...

Patients with Chronic Lymphocytic Leukemia (CLL) are known to have an increased incidence of second cancers, but the contribution of commonly used frontline therapies to the incidence of second cancers is unclear. We report on the characteristics, incidence, outcomes and factors associated with second cancers in 234 patients receiving Fludarabine, Cyclophosphamide, and Rituximab (FCR) based regimens in the frontline setting. The risk of second cancers was 2.38 times higher than the expected risk in the general population. Ninety three patients (40%) had other cancers before and 66 patients (28%) after FCR. The rates of t-AML/MDS (5.1%) and Richter’s transformation (RT) (9%) were high while solid tumors were not increased. Overall survival of patients with second cancers after frontline FCR was shorter (median of 4.5 years) compared to patients with and without prior cancers. Second cancer risk after frontline FCR is mainly due to high rates of t-AML/MDS and RT and as speculated the survival of affected patients is shorter.

Key Points Histologically aggressive CLL differs from histologically indolent CLL. Patients with different CLL phases but similar SUVmax have similar outcomes. FDG/PET is a useful diagnostic tool for patients with CLL and suspected transformation.

Previous studies have shown that B cell development is blocked at the pre-B cell stage in IFN regulatory factor (IRF)4 (pip) and IRF8 (IFN consensus sequence binding protein) double mutant mice (IRF4,8−/−). In this study, the molecular mechanism by which IRF4,8 regulate pre-B cell development was further investigated. We show that IRF4,8 function in a B cell intrinsic manner to control pre-B cell development. IRF4,8−/− mice expressing a Bcl-2 transgene fail to rescue pre-B cell development, suggesting that the defect in B cell development in IRF4,8−/− mice is not due to a lack of survival signal. IRF4,8−/− pre-B cells display a high proliferation index that may indirectly inhibit the L chain rearrangement. However, forced cell cycle exit induced by IL-7 withdrawal fails to rescue the development of IRF4,8−/− pre-B cells, suggesting that cell cycle exit by itself is not sufficient to rescue the development of IRF4,8−/− pre-B cells and that IRF4,8 may directly regulate the activation of L chain loci. Using retroviral mediated gene transduction, we show that IRF4 and IRF8 function redundantly to promote pre-B cell maturation and the generation of IgM+ B cells. Molecular analysis indicates that IRF4, when expressed in IRF4,8−/− pre-B cells, induces κ germline transcription, enhances V(D)J rearrangement activity at the κ locus, and promotes L chain rearrangement and transcription. Chromatin immunoprecipitation assay further reveals that IRF4 expression leads to histone modifications and enhanced chromatin accessibility at the κ locus. Thus, IRF4,8 control pre-B cell development, at least in part, by promoting the activation of the κ locus.

Tattooed nodes are visible intraoperatively, even months later. This approach obviates the need for additional localization procedures during axillary staging.

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Background Accelerated phase CML (CML-AP) most frequently represents a progression state in CML. However, some patients present with AP features at the time of diagnosis. There is limited information on the outcome of these patients when receiving tyrosine kinase inhibitors (TKI) as initial therapy. Methods We analyzed the outcome of 51 consecutive patients with CML who presented with features of AP at the time of diagnosis, including blasts ≥15% (n=6), basophils ≥20%, (n=22), platelets <100×109/L (n=3), cytogenetic clonal evolution (n=17), or more than 1 feature (n=3). Patients received initial therapy with imatinib (n=30), dasatinib (n=5) or nilotinib (n=16). Results The rate of complete cytogenetic response (CCyR) for patients treated with imatinib was 80%, and with dasatinib or nilotinib was 90%. Major molecular response (MMR, BCR-ABL/ABL ≤0.1%, by International Scale [IS]) was achieved in 69% including complete molecular responses (MR4.5, BCR-ABL/ABL ≤0.0032% IS) in 49%. MMR rates for patients treated with imatinib were 63%, and with second generation TKI (2GTKIs) 76%. Overall survival at 36 months was 87% with imatinib and 95% with 2GTKI’s. Conclusion TKIs should be considered standard initial therapy for patients with AP at the time of diagnosis.