Multiple myeloma (MM) is an incurable malignancy characterized by altered expression of coding and noncoding genes promoting tumor growth and drug resistance. Although the crucial role of long noncoding RNAs (lncRNAs) in MM is clearly established, the function of the noncoding RNAome, which might allow the design of novel therapeutics, is largely unknown. We performed an unbiased CRISPR-Cas9 loss-of-function screen of 671 lncRNAs in MM cells and their bortezomib (BZB)-resistant derivative. To rank functionally and clinically relevant candidates, we designed and used a bioinformatic prioritization pipeline combining functional data from cellular screens with prognostic and transcriptional data from patients with MM. With this approach, we unveiled and prioritized 8 onco-lncRNAs essential for MM cell fitness, associated with high expression and poor prognosis in patients with MM. The previously uncharacterized RP11-350G8.5 emerged as the most promising target, irrespective of BZB resistance. We (1) demonstrated the anti-tumoral effect obtained by RP11-350G8.5 inhibition in vitro and in vivo; (2) highlighted a modulation of the unfolded protein response and the induction of immunogenic cell death triggered by the RP11-350G8.5 knockout, via RNA sequencing and molecular studies; (3) characterized its cytoplasmic homing through RNA fluorescence in situ hybridization; and (4) predicted its 2-dimensional structure and identified 2 G-quadruplex and 3 hairpin-forming regions by biophysical assays, including thioflavin T, 1H nuclear magnetic resonance, and circular dichroism, to pave the way to the development of novel targeted therapeutics. Overall, we provided innovative insights about unexplored lncRNAs in MM and identified RP11-350G8.5 as an oncogenic target for treatment-naïve and BZB-resistant patients with MM.

The European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems are based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. This pooled analysis of the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to the 2017 and 2022 ELN risk classifications and derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on overall survival (OS). Overall, 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. The ELN 2017 or 2022 prognostic criteria classified most patients as adverse-risk AML (60.2% and 72.8% for venetoclax-azacitidine and 65.5% and 75.2% for placebo-azacitidine, respectively). Although outcomes with venetoclax-azacitidine improved across all ELN risk groups compared with placebo-azacitidine, ELN classification systems poorly discriminated venetoclax-azacitidine outcomes. By applying a bioinformatic algorithm, new molecular signatures were derived differentiating OS outcomes with venetoclax-azacitidine. The mutational status of TP53, FLT3 internal tandem duplication (FLT3-ITD), NRAS, and KRAS categorized patients into higher-, intermediate-, and lower-benefit groups (52%, 25%, and 23% of patients, respectively), each associated with a distinct median OS (26.5 months [95% confidence interval (CI), 20.2-32.7]; 12.1 months [95% CI, 7.3-15.2]; and 5.5 months [95% CI, 2.8-7.6], respectively). ELN prognostic classifiers did not provide clinically meaningful risk stratification of OS outcomes in patients treated with venetoclax-azacitidine. TP53, FLT3-ITD, NRAS, and KRAS mutation status allows the classification of these patients into 3 risk groups with distinct differences in median OS. These trials were registered at www.clinicaltrials.gov as #NCT02993523 and #NCT02203773.

With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate interstudy comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group-European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to (1) account for gender-specific differences in determining hemoglobin levels for eligibility criteria; (2) revise the definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices; and (3) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks before study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs non-TDA) and graded (major vs minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment.

Venous thromboembolism (VTE) is common among older individuals, but provoking factors are not identified in many cases. Patients with myeloid malignancies, especially myeloproliferative neoplasms (MPNs), are at increased risk for venous thrombosis. Clonal hematopoiesis of indeterminate potential (CHIP), a precursor state to myeloid malignancies, is common among older individuals and may similarly predispose to venous thrombosis. We evaluated overall and genotype-specific associations between CHIP and prevalent and incident VTE in >400 000 samples from the UK Biobank. CHIP was modestly associated with incident VTE with a hazard ratio (HR) of 1.17 (95% confidence interval [CI], 1.09-1.3; P = .002) but was not significantly associated with prevalent VTE with an odds ratio (OR) of 1.02 (95% CI, 0.81-1.23; P = .81). TET2-mutant CHIP was associated with incident VTE with a HR of 1.33 (95% CI, 1.05-1.69; P = .02). JAK2 mutations were highly associated with both prevalent and incident VTE risk, with an OR of 6.58 (95% CI, 2.65-16.29; P = 4.7 × 10-5) and a HR of 4.2 (95% CI, 2.18-8.08; P = 1.7 × 10-5), respectively, consistent with the thrombophilia associated with JAK2-mutant MPN. The association between JAK2-mutant CHIP and VTE remained significant after excluding potential undiagnosed MPN based on laboratory parameters. JAK2-mutant CHIP was more strongly associated with VTE but was less common than heterozygous factor V Leiden and heterozygous prothrombin gene mutation. These results indicate that most individuals with CHIP do not have an altered risk of thrombosis, but individuals with JAK2-mutant CHIP have a significantly elevated risk of VTE.