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Patients 70 years of age or younger with previously untreated CLL were randomly assigned to receive ibrutinib plus rituximab or chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The ibrutinib-based regimen led to prolonged progression-free and overall survival.

To understand immunomodulatory drug (IMiD) resistance in multiple myeloma (MM), we created isogenic human multiple myeloma cell lines (HMCLs) sensitive and resistant to lenalidomide, respectively. Four HMCLs were demonstrated to be resistant to all IMiDs including lenalidomide, pomalidomide, and CC-220, but not to Bortezomib. In three HMLCs (MM.1.SLenRes, KMS11LenRes and OPM2LenRes), CRBN abnormalities were found, including chromosomal deletion, point mutation, and low CRBN expression. The remaining HMCL, XG1LenRes, showed no changes in CRBN but exhibited CD147 upregulation and impaired IRF4 downregulation after lenalidomide treatment. Depletion of CD147 in XG1LenRes and three additional HMCLs had no significant impact on MM viability and lenalidomide response. Further analysis of XG1LenRes demonstrated increased IL6 expression and constitutive STAT3 activation. Inhibition of STAT3 with a selective compound (PB-1-102) re-sensitized XG1LenRes to lenalidomide. Since XG1LenRes harbors a truncated IRF4 that is not downregulated by lenalidomide, we targeted IRF4/MYC axis with a selective inhibitor of the bromodomain of CBP/EP300 (SGC-CBP30), which restored lenalidomide response in XG1LenRes. This strategy also appeared to be more broadly applicable as SGC-CBP30 could re-sensitize two resistant HMCLs with low but detectable CRBN expression to lenalidomide, suggesting that targeting CBP/E300 is a promising approach to restore IMiD sensitivity in MM with detectable CRBN expression.

Multiple myeloma (MM) is a heterogeneous disease characterized by frequent MYC translocations. Sporadic MYC activation in the germinal center of genetically engineered Vk*MYC mice is sufficient to induce plasma cell tumors in which a variety of secondary mutations are spontaneously acquired and selected over time. Analysis of 119 Vk*MYC myeloma reveals recurrent copy number alterations, structural variations, chromothripsis, driver mutations, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational activity, and a progressive decrease in immunoglobulin transcription that inversely correlates with proliferation. Moreover, we identify frequent insertional mutagenesis by endogenous retro-elements as a murine specific mechanism to activate NF-kB and IL6 signaling pathways shared with human MM. Despite the increased genomic complexity associated with progression, advanced tumors remain dependent on MYC . In summary, here we credential the Vk*MYC mouse as a unique resource to explore MM genomic evolution and describe a fully annotated collection of diverse and immortalized murine MM tumors. Mouse models often combine mutant alleles to accelerate cancer development, limiting oncogenic diversity. Here the authors show that sporadic MYC activation in Vk*MYC mice is sufficient to induce tumors with a variety of secondary mutations that mirror the genetic heterogeneity of human myeloma.

Monoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10−29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10−63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10−5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

Investigating venetoclax (VTX) resistance in multiple myeloma (MM) is crucial for the development of novel therapeutic strategies to tackle resistance. We conducted a multi-omic characterization of established VTX-resistant isogenic human myeloma cell lines (HMCL) and primary MM patient samples pre- and post-VTX treatment. Transcriptomic and proteomic analysis revealed that resistance was largely associated with BCL-2 family protein dysregulation, including upregulation of anti-apoptotic proteins such as MCL-1, BCL-XL, BCL-2, and downregulation of pro-apoptotic members. Notably, the re-introduction of BIM into resistant cells restored VTX sensitivity and synergized with MCL-1 inhibitors. Upstream signaling pathways, including growth factor receptor tyrosine kinase (RTK) and phosphoinositide-3-kinase (PI3K) were implicated in this dysregulation. Simultaneous inhibition of MCL-1, BCL-XL, and upstream PI3K, RTK (FGF, EGF, and IGF1) mediated signaling enhanced VTX sensitivity. Post-translational modifications of MCL-1, particularly its stabilization via acetylation and phosphorylation, were investigated, although their inhibition only marginally increased VTX sensitivity. Lastly, the inhibition of AURKA and mitochondrial respiration also improved VTX sensitivity in some resistant HMCLs. Our findings suggest that combining VTX with MCL-1 and BCL-XL inhibitors or PIK3/RTK inhibitors holds potential for overcoming resistance. The study illustrates the importance of understanding molecular determinants of resistance to develop tailored therapeutic strategies.

PurposeNUC1031 is a first-in-class ProTide, that is a gemcitabine pro-drug designed to overcome putative mechanisms of resistance, including decreased expression of hENT/hCNT transporters, absence of activating enzymes such as deoxycytidine kinase (dCK) and presence of degrading enzymes such as cytidine deaminase (CDA). We undertook comprehensive pre-clinical evaluation of NUC1031 in biliary tract cancer (BTC) models, given that gemcitabine/cisplatin is a standard first-line therapy in advanced BTC.MethodsHere, we compared the in vitro activity of NUC1031 in comparison to gemcitabine, validate putative mechanism(s) of action, assessed potential biomarkers of sensitivity or resistance, and performed combination studies with cisplatin. We also evaluated the in vivo efficacy of NUC1031 and gemcitabine using a CDA-high cholangiocarcinoma patient-derived xenograft (PDX) model.ResultsIn a panel of BTC cell lines (N = 10), NUC1031 had less potency than gemcitabine in multiple cellular assays. NUC1031 did not demonstrate evidence of greater synergy over gemcitabine in combination with cisplatin. Surprisingly, efficacy of both gemcitabine and NUC1031 was not found to be correlated with hENT/hCTN, dCK or CDA transcript levels. Gemcitabine and NUC1031 showed equivalent efficacy in a CDA-high PDX model in vivo contradicting the primary rationale of NUC1031 design.ConclusionNUC1031 did not exhibit evidence of superior activity over gemcitabine, as a single-agent, or in combination with cisplatin, in either our in vivo or in vitro BTC models. Given that the largest Phase 3 study (ClinicalTrials.gov: NCT0314666) to date in BTC is underway (N = 828) comparing NUC1031/cisplatin to gemcitabine/cisplatin, our results suggest that a more conservative clinical evaluation path would be more appropriate.

Fluorescence in situ hybridization (FISH) is currently the gold-standard assay to detect recurrent genomic abnormalities of prognostic significance in multiple myeloma (MM). Since most translocations in MM involve a position effect with heterogeneous breakpoints, we hypothesize that FISH has the potential to miss translocations involving these regions. We evaluated 70 bone marrow samples from patients with plasma cell dyscrasia by FISH and whole-genome mate-pair sequencing (MPseq). Thirty cases (42.9%) displayed at least one instance of discordance between FISH and MPseq for each primary and secondary abnormality evaluated. Nine cases had abnormalities detected by FISH that went undetected by MPseq including 6 tetraploid clones and three cases with missed copy number abnormalities. In contrast, 19 cases had abnormalities detected by MPseq that went undetected by FISH. Seventeen were MYC rearrangements and two were 17p deletions. MPseq identified 36 MYC abnormalities and 17 (50.0% of MYC abnormal group with FISH results) displayed a false negative FISH result. MPseq identified 10 cases (14.3%) with IgL rearrangements, a recent marker of poor outcome, and 10% with abnormalities in genes associated with lenalidomide response or resistance. In summary, MPseq was superior in the characterization of rearrangement complexity and identification of secondary abnormalities demonstrating increased clinical value compared to FISH.

MBL is a precursor condition to chronic lymphocytic leukemia (CLL), characterized by monoclonal B-cells in blood. Mosaic chromosomal alterations (mCAs) are a form of clonal hematopoiesis that include gains, losses, and copy-neutral loss-of-heterozygosity of large DNA segments. Both MBL and mCAs have been found to increase the risk of CLL and lymphoid malignancies, and the aim of our study was to investigate how mCAs relate to MBL, which is currently unknown. We analyzed genetic, flow cytometric, and hematologic data from 4632 individuals from the Mayo Clinic Biobank and CLL Database. MBL was detected using flow cytometry and classified as high-count (HC) or low-count (LC) MBL based on clone size. mCAs were detected primarily from whole blood DNA using sensitive SNP-array-based analyses. mCAs commonly altered in CLL (deletion of 6q, 11q, 13q, 17p, and trisomy 12) were specific (>99%) to individuals with MBL and CLL. HC-MBL and LC-MBL individuals were 881-fold and 8-fold, respectively, more likely to harbor CLL-associated mCAs than those without MBL. The cell fraction bearing these mCAs typically exceeded the B-cell fraction, suggesting their origin prior to the B-cell lineage. Integrating genetic and blood count data enabled detecting HC-MBL with high specificity in a biobank sample. These results quantify the contribution of mCAs to MBL and could enable large studies of HC-MBL without the need for flow cytometric screening.