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BackgroundExportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood.MethodsWe performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations in XPO1 (predominantly E571K or E571G; n = 72) with genetic and epigenetic features contributing to the overall outcomes in these patients. We then established a mouse model with over-expression of wildtype (wt) or mutant (E571K or E571G) XPO1 restricted to the B cell compartment (Eµ-XPO1). Eµ-XPO1 mice were then crossed with the Eµ-TCL1 CLL mouse model. Lastly, we determined crystal structures of XPO1 (wt or E571K) bound to several selective inhibitors of nuclear export (SINE) molecules (KPT-185, KPT-330/Selinexor, and KPT-8602/Eltanexor).ResultsWe report that nonsynonymous mutations in XPO1 associate with high risk genetic and epigenetic features and accelerated CLL progression. Using the newly-generated Eµ-XPO1 mouse model, we found that constitutive B-cell over-expression of wt or mutant XPO1 could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression of XPO1 with E571K or E571G mutations and TCL1 accelerated the rate of leukemogenesis relative to that of Eµ-TCL1 mice. Lastly, crystal structures of E571 or E571K-XPO1 bound to SINEs, including Selinexor, are highly similar, suggesting that the activity of this class of compounds will not be affected by XPO1 mutations at E571 in patients with CLL.ConclusionsThese findings indicate that mutations in XPO1 at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.

Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.

Little is known about outcomes of patients with chronic lymphocytic leukemia (CLL) with del(17p13.1) karyotype at diagnosis. We reviewed 114 de novo del(17p13.1) CLL patients seen at our institution. Using proportional hazards models to identify pretreatment clinical variables significantly associated with treatment-free survival (TFS) and overall survival (OS), we developed a simplified risk score for de novo del(17p13.1) CLL patients to predict TFS and OS based on these variables. These scores, particularly the very highest, can be utilized to identify high-risk patients for expedient enrollment on clinical trials. Our data support careful observation for low-risk patients, potentially preventing unnecessary use of aggressive therapies.

BackgroundTrisomy 12 (+12) is detected by fluorescence in-situ hybridization (FISH) analysis in up to 20% of patients with chronic lymphocytic leukemia (CLL). Patients with +12 are known to have unique features and to carry an intermediate prognosis.Patients and methodsIn order to better define this large group, we reviewed the characteristics of 250 untreated patients with +12.ResultsWhen compared to 516 untreated patients negative for +12 by FISH, patients with +12 showed a higher incidence of thrombocytopenia, Richter transformation, and second malignant neoplasms (SMN), in addition to the expected increased rate of CD38 positivity and atypical immunophenotype. At a median follow-up of 51 months, 57% of patients needed first-line treatment; median time to first treatment was 38 months, and on multivariate analysis (MVA), it was found to be shorter in patients with advanced Rai stage, palpable splenomegaly, and deletion of 14q by conventional cytogenetic analysis. The overall response rate with first-line treatment was 94%. The median failure-free survival has not been reached, but on MVA, it was found to be shorter in patients whose disease responded in a manner other than complete remission or with FISH negativity for deletion 13q. The median overall survival for the entire group has not been reached, but MVA revealed it to be shorter in patients with an absolute lymphocyte count of > 30 × 10(9)/L or who developed SMN. Eighteen deaths have been observed so far, and Richter transformation and SMN were the leading causes of death (3 and 6, respectively).ConclusionPatients with +12 CLL show characteristic clinical and biologic features, and may benefit from increased surveillance for second cancers.

Allogeneic stem cell transplant (alloSCT) can overcome the adverse prognosis of chronic lymphocytic leukemia with 17p deletion (17p- CLL). However, its applicability remains unclear. Since 2007, our leukemia service has referred patients with 17p- CLL for alloSCT at presentation. In this study, the outcomes of these patients were reviewed retrospectively to determine whether they underwent alloSCT and why patients did not undergo alloSCT. Fifty-two patients with 17p- CLL who were referred to the transplant service from 2007 to 2010 were identified. Of these patients, 32 (62%) did not undergo alloSCT, mainly because of treatment- or disease-related complications (n = 15). The 2-year post-referral overall survival rates of the alloSCT and non-SCT groups were 64% and 25%, respectively (p = 0.001). These findings suggest that while alloSCT is an effective therapy in patients with 17p- CLL, pre-SCT complications may preclude a significant proportion of patients from undergoing the procedure.

Background: There have been many recent breakthroughs in processing and analyzing large-scale data sets in biomedical informatics. For example, the CytoGPS algorithm has enabled the use of text-based karyotypes by transforming them into a binary model. However, such advances are accompanied by new problems of data sparsity, heterogeneity, and noisiness that are magnified by the large-scale multidimensional nature of the data. To address these problems, we developed the Mercator R package, which processes and visualizes binary biomedical data. We use Mercator to address biomedical questions of cytogenetic patterns relating to lymphoid hematologic malignancies, which include a broad set of leukemias and lymphomas. Karyotype data are one of the most common form of genetic data collected on lymphoid malignancies, because karyotyping is part of the standard of care in these cancers. Results: In this paper we combine the analytic power of CytoGPS and Mercator to perform a large-scale multidimensional pattern recognition study on 22,741 karyotype samples in 47 different hematologic malignancies obtained from the public Mitelman database. Conclusion: Our findings indicate that Mercator was able to identify both known and novel cytogenetic patterns across different lymphoid malignancies, furthering our understanding of the genetics of these diseases. [ABSTRACT FROM AUTHOR]

The article presents research on the role of t(14;19)(q32;q13) chromosomal translocation in B-cell leukemias and lymphomas. Chronic lymphocytic leukemia (CLL) cases associated with t(14;19) often exhibit morphologic and immunophenotypic features and unmutated immunoglobulin heavy chain (IGH) variable region (V) genes. An analysis of IGHV somatic mutation status and gene use in 11 patients with t(14;19)-positive CLL was conducted. A possibility exists that a specific antigen drive is involved in CLL formation.

Summary: Follicular lymphomas characteristically carry t(14;18)(q32;q21) which results in IGH-BCL-2 fusion. Variant translocations that juxtapose the BCL-2 gene with the immunoglobulin κ (2p11) and λ (22q11) light chain genes are rare. We report 4 cases of B-cell lymphoma/leukemia associated with t(18;22)(q21;q11). The t(18;22)(q21;q11) was the sole aberration identified by conventional cytogenetics in 2 cases. Three cases were classified as chronic lymphocytic leukemia, and one as follicular lymphoma based on morphology and immunophenotype. Fluorescence in situ hybridization analysis was performed on all 4 cases using a BCL-2 breakapart probe. The BCL-2 gene was rearranged in all cases. Immunoglobulin λ light chain gene rearrangement was shown in 3 cases using bacterial artificial chromosome probes spanning the variable and constant clusters of the IGλ gene. Each case was negative for MALT-1 rearrangement using a MALT-1 breakapart probe. These cases illustrate that t(18;22)(q21;q11) is more commonly observed in chronic lymphocytic leukemia and may represent either an initial or secondary genetic event. [Copyright &y& Elsevier]

The t(14;19)(q32;q13), involving the BCL3 locus at chromosome 19q13 and the immunoglobulin heavy chain gene at 14q32, is a rare recurrent cytogenetic abnormality identified in B-cell neoplasms, most of which have been classified as chronic lymphocytic leukaemia (CLL) in the literature. We describe the clinicopathological, immunophenotypic and cytogenetic findings in seven patients with B-cell neoplasms associated with t(14;19)(q32;q13). There were five men and two women, with a median age of 48 years (range 33–68). All had absolute lymphocytosis, six had lymphadenopathy, and one had splenomegaly. Lymphocytes in blood and bone marrow aspirate smears were predominantly small and cytologically atypical. Flow cytometric immunophenotyping showed an atypical immunophenotype with low CLL scores. The growth pattern in bone marrow biopsy specimens was interstitial to diffuse; immunohistochemical stains were positive for bcl3 and negative for cyclin D1. Lymph node biopsy specimens of two patients revealed total architectural effacement by neoplasm with proliferation centres. In addition to t(14;19), cytogenetic studies demonstrated trisomy 12 in five patients. These results suggest that B-cell neoplasms with the t(14;19)(q32;q13) present frequently as leukaemia composed of small B-lymphocytes and share many features with CLL. However, these neoplasms also differ from CLL cytologically and in their immunophenotype. [ABSTRACT FROM AUTHOR]