Mark Murakami

• MD
• Dana-Farber Cancer Institute

Background Adhesion molecules within the bone marrow vascular niche govern the self-renewal, differentiation, and proliferation of hematopoietic progenitors. Among these, E-selectin, a lectin expressed by endothelial cells which binds to the tetrasaccharide known as sialyl Lewis X (sLeX), promotes dormancy, self-renewal, and chemoresistance in nati...

Achieving undetectable minimal residual disease (uMRD) is rare with B-cell receptor (BCR) targeting in chronic lymphocytic leukemia (CLL). We have reported interim results of a phase 2 study combining acalabrutinib with the PI3K inhibitor umbralisib for 6 months, followed by the addition of the anti-CD20 antibody ublituximab (AU2) for months 7-12,...

Background: People with immune suppression due to HIV, congenital conditions, or immunosuppressive therapy are at higher risk for aggressive B-cell lymphomas. In many low-resource areas, such as sub-Saharan Africa, this cancer risk is compounded by delayed diagnoses due to several key factors. Firstly, diagnostic confounding or misdiagnosis of lymp...

Introduction: Patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) have few treatment options. TP53-aberrant treatment naïve (TN) MCL is associated with inferior outcomes (Eskelund, Blood 2017). There is interest in chemotherapy-free regimens for older, transplant-ineligible (TI) TN pts. The combination of the Bruton tyrosine ki...

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poo...

Cell density, the ratio of cell mass to volume, is an indicator of molecular crowding and therefore a fundamental determinant of cell state and function. However, existing density measurements lack the precision or throughput to quantify subtle differences in cell states, particularly in primary samples. Here we present an approach for measuring th...

Lymphoma, a leading cancer cause of death among people living with HIV (PLHIV) globally, poses a pressing public health challenge in Sub-Saharan Africa (SSA), the epicentre of the HIV epidemic. Despite its prevalence, the genetic underpinnings of lymphoma in Black Africans and PLHIV remain poorly defined, contributing to regional disparities. This...

The optimal use of many biotherapeutics is restricted by Anti-drug antibodies (ADAs) and hypersensitivity responses which can affect potency and ability to administer a treatment. Here we demonstrate that Re-surfacing can be utilized as a generalizable approach to engineer proteins with extensive surface residue modifications in order to avoid bind...

Introduction Oral tyrosine kinase inhibitors (TKIs) that inhibit the constitutively active ABL1 kinase have improved outcomes for BCR-ABL1+ acute lymphoblastic leukemia (ALL) and decreased reliance on cytotoxic chemotherapy (ctx). Later generation, more potent TKIs such as dasatinib (DAS) are particularly effective (Foa et al. Blood 2011; Foa et al...

Background: The concept of multi-step carcinogenesis (Fearon and Vogelstein 1990) suggests that acquisition of mutations in addition to an existing set of mutations invariably accelerates tumor-progression. In colorectal cancer and many other cancer types, activation of multiple distinct oncogenic pathways is required for the development of invasiv...

Targeted inhibitors of essential oncogenic kinases induce high rates of clinical response but cure few patients due to the persistence of minimal residual disease (MRD). BCR-ABL mutant leukemias are a classic example of this paradigm where patients usually achieve deep remissions followed by near inevitable relapses. Multiple factors have been show...

Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer¹. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the diff...

Malignant transformation typically involves multiple genetic lesions whose combined activity gives rise to cancer1. Our analysis of 1,148 patient-derived B-cell leukemia (B-ALL) samples revealed that individual mutations did not promote leukemogenesis unless they converged on one single oncogenic pathway characteristic for the differentiation statu...

Background and significance: Normal B-cells constantly exchange information with their environment and depend on external cues for proliferation and survival that engage multiple divergent pathways (e.g. cytokine receptors; B-cell receptor, BCR). The dependency of normal B-cells on signaling input from a diverse repertoire of surface receptors is i...

Introduction The BCR-ABL1 gene fusion is the most common molecular aberration in adult ALL and confers an adverse prognosis. The incorporation of ABL1 tyrosine kinase inhibitors (TKIs) into ALL chemotherapy regimens has dramatically improved outcomes for BCR-ABL1+ ALL. Subsequently, reduced-intensity TKI-based regimens have been shown to be as effe...

Targeted inhibitors of oncogenic kinases have transformed cancer therapy by inducing high rates of clinical response across diverse tumor types, yet they cure few patients due to the persistence of minimal residual disease (MRD), which seeds relapse. Characterizing MRD biology would promote development of more effective therapies tailored to relaps...

Cambridge Core - Medicine: General Interest - Anemia - edited by Edward J. Benz, Jr.

Key Points Inhibition of BTK in patients who are resistant to ibrutinib changes signaling tumor dependencies and promotes MYC upregulation. Multitarget inhibition of LYN, FYN, and BLK is therapeutically effective in patients with DLBCL independent of their molecular subtypes.

Therapeutics that block kinases, transcriptional modifiers, immune checkpoints and other biological vulnerabilities are transforming cancer treatment. As a result, many patients achieve dramatic responses, including complete radiographical or pathological remission, yet retain minimal residual disease (MRD), which results in relapse. New functional...

p>Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study tumor evolution, mechanisms of drug response and resistance, and tailoring chemotherapeutic approaches for individual patients. The lack of robust standards for reporting on PDX models has hampered the ability of researchers to find...

p>Preclinical models of paediatric solid tumours that could help identify predictive biomarkers of a patient's sensitivity to therapy have been lacking. Over five years, the authors have developed an open access collection of orthotopic xenografts of 12 types of paediatric tumour. Genomic and epigenetic characterization reveals that xenografts reta...

Lymphomas represent nearly 70 distinct diseases with unique clinical presentations, therapeutic responses and underlying biology. There is a pressing shortage of publically available cell line and in vivo models of nearly all of these diseases; T-cell lymphoma models are particularly under-represented compared to B-cell lymphomas, which has severel...

Assays that can determine the response of tumor cells to cancer therapeutics could greatly aid the selection of drug regimens for individual patients. However, the utility of current functional assays is limited, and predictive genetic biomarkers are available for only a small fraction of cancer therapies. We found that the single-cell mass accumul...

Methods to rapidly assess cell growth would be useful for many applications, including drug susceptibility testing, but current technologies have limited sensitivity or throughput. Here we present an approach to precisely and rapidly measure growth rates of many individual cells simultaneously. We flow cells in suspension through a microfluidic cha...

(Cancer Cell 29, 574–586; April 11, 2016) In the originally published version of this article, coauthor Andrew M. Intlekofer was listed incorrectly as Andrew M. Intlekoffer and coauthor Nicole R. LeBoeuf was listed incorrectly as Nicole LaBoeuf. These errors have now been corrected here and in the article online. The authors apologize for the error...

Introduction: Unplanned hospitalizations are common in patients with cancer, and most hospitalizations originate in the emergency department (ED). Methods: We implemented an ED-based pilot intervention designed to reduce hospitalizations among patients with solid tumors. The intervention, piloted at a single academic medical center, involved a m...

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repo...

To expedite the translation of biologic discoveries into novel therapeutics, there is a pressing need for panels of in vivo models that capture the molecular complexity of human disease. While traditional cell lines and genetically engineered mouse models are useful tools, they are insufficient to assess the broad diversity of human tumors within a...

Lymphomas represent nearly 70 distinct diseases with unique clinical presentations, therapeutic responses and underlying biology. There is a pressing shortage of publically available cell line and in vivo models of nearly all of these diseases, which has severely hampered efforts to understand and target their biology. To address this issue, we hav...

The majority of drugs tested in clinical trials for hematologic malignancies ultimately fail to confer benefit. In many cases, this results from the inability to accurately identify patients most likely to benefit and mechanisms that mediate resistance. At the same time, clinical trials commonly fail to capture essential specimens at early and late...

Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. We did DNA deep sequencing to retrospectivel...

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis that in many cases is caused by mutations of the ELANE gene, which encodes neutrophil elastase (NE). Recent data suggest a model in which ELANE mutations result in NE protein misfolding, induction of endoplasmic reticulum (ER) stress, activation of the unfolded protein resp...

551 Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis characterized by chronic neutropenia, a block in granulocytic differentiation at the promyelocyte/myelocyte stage, and a marked propensity to develop acute myeloid leukemia. Approximately 50% of cases of SCN are associated with germline heterozygous mutations of ELA2, e...

Acute promyelocytic leukemia (APL) is characterized by the t(15;17) chromosomal translocation, which results in fusion of the retinoic acid receptor alpha (RARA) gene to another gene, most commonly promyelocytic leukemia (PML). The resulting fusion protein, PML-RARA, initiates APL, which is a subtype (M3) of acute myeloid leukemia (AML). In this re...

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis characterized by chronic neutropenia, a block in granulocytic differentiation at the promyelocyte/myelocyte stage, and a marked propensity to develop acute myeloid leukemia. Most cases of SCN are associated with germline heterozygous mutations of ELA2, encoding neutrophil e...

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Mutations of the ELA2 gene encoding neutrophil elastase (NE) are responsible for most cases of SCN and cyclic neutropenia (CN), a related but milder disorder of granulopoiesis. However, the mechanisms by which these mutations disrupt granulopoiesis are unclear. We hypothes...

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Mutations of ELA2, encoding neutrophil elastase (NE), are present in approximately 50% of cases of SCN. To date, 52 distinct, mostly missense, mutations of ELA2 have been identified. The diversity of ELA2 mutations in SCN and lack of consistent effect of these mutations on...

The membrane skeleton of the Tetrahymena is likely to determine many aspects of the cell surface structure of this ciliated protozoan. The availability of the genomic sequence of Tetrahymena thermophila has facilitated a proteomic analysis of the non-microtubular portion of the cortical cytoskeleton of Tetrahymena thermophila. Potassium iodide-Trit...