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In this study, investigators identified activating mutations in BRAF (specifically V600E, which is also present in some melanomas and thyroid cancers) in all 48 patients with hairy-cell leukemia who were evaluated. Hairy-cell leukemia (HCL) is a distinct disease entity that is characterized by an indolent course, marked splenomegaly, progressive pancytopenia in many cases, and rare circulating tumor cells, usually with no lymphadenopathy. 1 The bone marrow, spleen, and liver are characteristically infiltrated by leukemic B cells that have abundant cytoplasm with hairy-looking projections and unique immunophenotypic features. 2 , 3 Currently, the treatment of HCL is based on highly effective purine nucleoside analogues. 4 In spite of the remarkable progress in the diagnosis and treatment of HCL during the past 50 years, the underlying genetic alterations that cause the disease remain obscure. 3 Major obstacles to . . .

NOTCH1 mutations in chronic lymphocytic leukemia (CLL) lead to accumulation of NOTCH1 intracellular domain (NICD) and prolong signaling. These mutations associate with a more aggressive disease compared to wild-type (WT) CLL. In this work we demonstrate a bidirectional functional relationship between NOTCH1 and the B cell receptor (BCR) pathways. By using highly homogeneous cohorts of primary CLL cells, activation of NOTCH1 is shown to increase expression of surface IgM, as well as LYN, BTK, and BLNK, ultimately enhancing BCR signaling responses, including global mRNA translation. Upon BCR cross-linking, NOTCH1 itself is actively translated and increased on cell surface. Furthermore, BCR ligation induces calcium mobilization that can facilitate ligand-independent NOTCH1 activation. These data suggest that the two pathways are functionally linked, providing a rationale for dual inhibition strategies. Consistently, addition of the γ-secretase inhibitor DAPT to ibrutinib significantly potentiates its effects, both in vitro and in a short-term patient-derived xenograft model. While this observation may find limited applications in the CLL field, it is more relevant for Richter’s Syndrome (RS) management, where very few successful therapeutic options exist. Treatment of RS-patient-derived xenografts (RS-PDX) with the combination of ibrutinib and DAPT decreases disease burden and increases overall survival.

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

In follicular lymphoma (FL), surface immunoglobulin (sIg) carries mandatory N-glycosylation sites in the variable regions, inserted during somatic hypermutation. These glycosylation sites are tumor-specific, indicating a critical function in FL. Added glycan unexpectedly terminates at high mannose (Mann) and confers capability for sIg-mediated interaction with local macrophage-expressed DC-SIGN lectin resulting in low-level activation of upstream B-cell receptor signaling responses. Here we show that despite being of low-level, DC-SIGN induces a similar downstream transcriptional response to anti-IgM in primary FL cells, characterized by activation of pathways associated with B-cell survival, proliferation and cell–cell communication. Lectin binding was also able to engage post-transcriptional receptor cross-talk pathways since, like anti-IgM, DC-SIGN down-modulated cell surface expression of CXCR4. Importantly, pre-exposure of a FL-derived cell line expressing sIgM-Mann or primary FL cells to DC-SIGN, which does not block anti-IgM binding, reversibly paralyzed the subsequent Ca 2+ response to anti-IgM. These novel findings indicate that modulation of sIg function occurs in FL via lectin binding to acquired mannoses. The B-cell receptor alternative engagement described here provides two advantages to lymphoma cells: (i) activation of signaling, which, albeit of low-level, is sufficient to trigger canonical lymphoma-promoting responses, and (ii) protection from exogenous antigen by paralyzing anti-IgM-induced signaling. Blockade of this alternative engagement could offer a new therapeutic strategy.

Prognostication in patients with chronic lymphocytic leukemia (CLL) is challenging due to heterogeneity in clinical course. We hypothesize that constitutional genetic variation affects disease progression and could aid prognostication. Pooling data from seven studies incorporating 842 cases identifies two genomic locations associated with time from diagnosis to treatment, including 10q26.13 (rs736456, hazard ratio (HR) = 1.78, 95% confidence interval (CI) = 1.47–2.15; P  = 2.71 × 10 −9 ) and 6p (rs3778076, HR = 1.99, 95% CI = 1.55–2.55; P  = 5.08 × 10 −8 ), which are particularly powerful prognostic markers in patients with early stage CLL otherwise characterized by low-risk features. Expression quantitative trait loci analysis identifies putative functional genes implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. In this work we identify rs736456 and rs3778076 as prognostic in CLL, demonstrating that disease progression is determined by constitutional genetic variation as well as known somatic drivers. The clinical course of chronic lymphocytic leukaemia (CLL) is variable and difficult to predict. Here, the authors conduct a genome wide association study meta-analysis for time to first treatment in CLL patients and report two loci associating with progressive disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cancer is a clonal evolutionary process, caused by successive accumulation of genetic alterations providing milestones of tumor initiation, progression, dissemination, and/or resistance to certain therapeutic regimes. To unravel these milestones we propose a framework, tumor evolutionary directed graphs (TEDG), which is able to characterize the history of genetic alterations by integrating longitudinal and cross-sectional genomic data. We applied TEDG to a chronic lymphocytic leukemia (CLL) cohort of 70 patients spanning 12 years and show that: (a) the evolution of CLL follows a time-ordered process represented as a global flow in TEDG that proceeds from initiating events to late events; (b) there are two distinct and mutually exclusive evolutionary paths of CLL evolution; (c) higher fitness clones are present in later stages of the disease, indicating a progressive clonal replacement with more aggressive clones. Our results suggest that TEDG may constitute an effective framework to recapitulate the evolutionary history of tumors. A historical event is often the culmination of the preceding circumstances. The same can be said of cancer as a disease. Cancer results from genetic mutations that disrupt the normal biological processes within a cell, removing the fail-safes that prevent it from growing and reproducing uncontrollably. Cancer is not caused by just one mutation, and once one gene is malfunctioning, other genes become much more likely to mutate. Although modern sequencing methods have revealed many of the genes that mutate in several different kinds of cancer, uncovering when each of these mutations occurs has been more difficult. Knowing when each mutation occurs could make it easier to predict how the cancer will progress and could also help target cancer treatments more effectively. Wang, Khiabanian, Rossi et al. have devised a new method of studying the history of genetic mutations of cancer patients. This combines a ‘longitudinal’ method that looks at how mutations develop in a single tumor by taking samples from it at different times and ‘cross-sectional’ methods that make predictions based on data collected from a large number of patients. Wang, Khiabanian, Rossi et al. call this method ‘tumor evolutionary directed graphs’ (TEDG), as it produces a graph that shows how different gene mutations are related to each other. Initial tests showed that the TEDG method could accurately decipher the main chain of events in cancer evolution when used on data collected from at least 30 patients. Wang, Khiabanian, Rossi et al. then used TEDG on data from 164 tumor samples collected over 12 years from 70 patients with chronic lymphocytic leukemia, the type of leukemia that is most widespread amongst adults in Western countries. This uncovered two separate ways that this cancer may develop, one of which has a higher risk of life-threatening complications. Knowing which of the two ways chronic lymphocytic leukemia is progressing in a patient could help treat the disease, as each pathway responds differently to different treatments. In addition, understanding the paths that cancer progression follows could also provide early warning signals of the mutations that will occur next. This could help to develop alternative, targeted cancer treatments.

A man with refractory hairy-cell leukemia had a major response to inhibition of BCL2 with venetoclax, with both hematologic and functional improvement.

Among patients with previously untreated chronic lymphocytic leukemia, ibrutinib–venetoclax therapy with treatment duration guided by measurable residual disease status resulted in better outcomes than standard chemotherapy.