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We examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eightyfour of 807 (10.4%) cases, mainly using the IGHV3-21 and IGHV4-34 genes, were found to bear stereotyped heavy complementaritydetermining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23.Comparison with other entities, in particular CLL, revealed that several of these mutations were "MCL-biased." In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases. (Blood. 2011; 118(11):3088-3095) IntroductionMantle cell lymphoma (MCL) is an aggressive B-cell malignancy that represents 5%-10% of non-Hodgkin lymphomas. The median overall survival is 3-5 years, and at present, conventional treatment is not curative and long-term remission is rare. However, subsets of MCL patients follow a more indolent clinical course without disease progression for a relatively long period. 1 The cytogenetic hallmark of MCL is the chromosomal translocation t(11;14)(q13;q32). This aberration leads to the juxtaposition of the CCDN1 locus on chromosome 11 to the immunoglobulin heavy chain (IGH) locus on chromosome 14. As a consequence, cyclin D1 is constitutively overexpressed, causing gross cell cycle deregulation. 2 In addition to the primary t(11;14), several secondary genomic aberrations can be identified in most MCL cases, 2,3 supporting early findings that cyclin D1 overexpression must be accompanied by other genetic abnormalities to promote lymphomagenesis. 2,4 Various gene expression changes that may cooperate with cyclin D1 deregulation also have been described in MCL, mainly involved in DNA repair pathways and the control of cell cycle and apoptosis. 4,5 That notwithstanding, alterations in the local tumor microenvironment also may play an important role in regulating the growth and survival of MCL neoplastic cells. 2,5,6 In B-cell malignancies, immunogenetic analysis of the clonogenic B-cell receptors (BcRs) offers valuable insight into both the ontogenetic derivation and the possible involvement of antigen selection. In particular, a biased repertoire of immunoglobulin heavy variable (IGHV) genes is generally considered as evid...

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Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared with JAK3 or HOXA9 alone. Integrated RNA sequencing, chromatin immunoprecipitation sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) revealed that STAT5 and HOXA9 have co-occupancy across the genome, resulting in enhanced STAT5 transcriptional activity and ectopic activation of FOS/JUN (AP1). Our data suggest that oncogenic transcription factors such as HOXA9 provide a fertile ground for specific signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9-expressing cells. The mechanism of oncogene cooperation in cancer development remains poorly characterized. In this study, we model the cooperation between activated JAK/STAT signaling and ectopic HOXA9 expression during T-cell leukemia development. We identify a direct cooperation between STAT5 and HOXA9 at the transcriptional level and identify PIM1 kinase as a possible drug target in mutant JAK/STAT/HOXA9-positive leukemia cases. .

The function of the intracellular protein hematopoietic cell-specific Lyn substrate-1 (HS1) in B lymphocytes is poorly defined. To investigate its role in migration, trafficking, and homing of leukemic B lymphocytes we have used B cells from HS1 ؊/؊ mice, the HS1-silenced human chronic lymphocytic leukemia (

We performed an immunogenetic analysis of 345 IGHV --IGHD --IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; 12.8%; 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele *04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2*04 peaked at 31%. The IGHV1-2*04 rearrangements carried significantly longer complementaritydetermining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2*04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97 --99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2*04 allele.

Key Points The prevalence of MBL among blood donors is much higher than previously reported. Although uncommon, higher-risk MBL phenotypes and genotypes were observed.

Key Points• Low-count and high-count monoclonal B-cell lymphocytosis (MBL) have distinct immunogenetic signatures, with only the latter resembling CLL.• Rather than a true premalignant condition, low-count MBL may merely reflect immune senescence or result from persistent antigen stimulation.Chronic lymphocytic leukemia (CLL) -like monoclonal B-cell lymphocytosis (MBL) shares common immunophenotype and cytogenetic abnormalities with CLL, from which it is discriminated by a cutoff value of 5 3 10 9 /L circulating clonal B cells. However, the clonal size in MBL is extremely variable and allows discrimination of two distinct entities (highcount [HC] and low-count [LC]-MBL) based on a cutoff value of 0.5 3 10 9 /L clonal B cells. HC-MBL is associated with lymphocytosis and progresses to CLL requiring treatment at a rate of 1.1% per year, whereas LC-MBL is found in the general population only through high-sensitivity techniques and carries limited, if any, risk of progression. We performed an immunogenetic profiling of 333 cases with CLL-like MBL supplemented by detailed comparisons with CLL, focusing especially on CLL Rai stage 0 (CLL-0). LC-and HC-MBL had similar somatic hypermutation status, yet different IGHV gene repertoires and frequencies of B-cell receptor (BcR) stereotypy. In particular, stereotyped BcRs were infrequent in LC-MBL and were often not CLL specific. In contrast, HC-MBL exhibited clear immunogenetic similarities to CLL-0. These findings indicate that LC-MBL may not represent a true preleukemic condition, thus differing from HC-MBL/CLL-0 in which the identification of factors endowing malignant potential is strongly warranted. (Blood. 2013; 121(22):4521-4528)