Jonathan A. Gutman

Double unit cord blood transplantation: Who wins-and why do we care?

Double unit cord blood transplantation (DUCBT) has emerged as a successful strategy to improve engraftment and decrease transplant related mortality in adults and large children undergoing cord transplantation. In the vast majority of cases, one unit emerges as the sole source of long term hematopoiesis in the recipient following DUCBT. No factors have been identified that reliably predict which unit will emerge as the dominant unit, and limited studies have examined the mechanism underlying the observation. In a recent publication in Blood, we provide the first compelling data that effector CD8+ T cells play a critical role in the dominant unit actively rejecting the losing unit. Our findings provide an important first step in understanding the interactions following DUCBT, and provide insights that might be used to optimize graft versus leukemia effect and cord unit selection as well as better understand mechanisms of tolerance.

Rational Design of a Parthenolide-based Drug Regimen that Selectively Eradicates Acute Myelogenous Leukemia Stem Cells.

Although multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles. Rather, drug combinations are largely dictated by empirical or clinical parameters. In the present study we developed a strategy for rational design of a regimen that selectively targets human acute myelogenous leukemia (AML) stem cells. As a starting point, we used parthenolide, an agent shown to target critical mechanisms of redox balance in primary AML cells. Next, using proteomic, genomic, and metabolomic methods, we determined that treatment with parthenolide leads to induction of compensatory mechanisms that include up-regulated NADPH production via the pentose phosphate pathway as well as activation of the Nrf2-mediated oxidative stress response pathway. Using this knowledge we identified 2-deoxyglucose and temsirolimus as agents that can be added to a parthenolide regimen as a means to inhibit such compensatory events and thereby further enhance eradication of AML cells. We demonstrate that the parthenolide, 2-deoxyglucose, temsirolimus (termed PDT) regimen is a potent means of targeting AML stem cells but has little to no effect on normal stem cells. Taken together our findings illustrate a comprehensive approach to designing combination anticancer drug regimens.

Changes in allele frequencies of CSF3R and SETBP1 mutations and evidence of clonal evolution in a chronic neutrophilic leukemia patient treated with ruxolitinib

In 2008, the World Health Organization (WHO) recognized the BCR-ABL1 negative myeloproliferative neoplasm (MPN) chronic neutrophilic leukemia (CNL) as a distinct entity based on the features of an increased white blood cell count (WBC) with a preponderance of neutrophils, no increase in blasts, no

Clonality of neutrophilia associated with plasma cell neoplasms: report of a SETBP1 mutation and analysis of a single institution series.

Abstract A rare but well-known association between plasma cell neoplasms and neutrophilia is known to exist. Whether the neutrophilia is secondary to the plasma cell neoplasm or this convergence represents two independent clonal disorders is unclear. We reviewed five consecutive cases from a single institution over a 3-year period, applying molecular, cytogenetic and cytokine-profiling approaches to determine whether neutrophilia associated with plasma cell neoplasms represents a reactive or clonal process. We report, for the first time, the occurrence of a SETBP1 mutation in two cases, as well as changes in G-CSF and IL-6 in SETBP1 wild type vs. mutated patients that are supportive of a hypothesis that neutrophilia associated with plasma cell neoplasms may sometimes be reactive and may sometimes represent a second clonal entity. Finally, using an ex vivo drug screening platform we report the potential efficacy of the multi-kinase inhibitor dasatinib in select patients.

Stopping Higher-Risk Myelodysplastic Syndrome in Its Tracks

Higher-risk myelodysplastic syndromes (MDS) are a collection of diseases associated with poor outcomes from complications related to bone marrow failure and evolution to acute myeloid leukemia. While most patients receive epigenetic therapies, intensive chemotherapy or allogeneic stem cell transplantation, more tolerable and effective treatments are necessary to realize the goal of stopping this disease in its tracks. Recent efforts, building on decades of research exploring the pathogenesis of this disease, have revealed exciting clues that elucidate critical biological features that drive or contribute to MDS, and may serve as targets for selective and well-tolerated future therapies. Here, we review the current diagnostic, prognostic, and therapeutic approaches to higher-risk MDS.

A novel CCAAT/enhancer binding protein α germline variant in a case of acute myeloid leukemia

CCAAT/enhancer binding protein α (CEBPA) is a transcription factor with a pivotal role in control of proliferation and diff erentiation of myeloid progenitors. Th e CEBPA protein consists of two N-terminal transcription domains (TAD1 and TAD2), a basic region able to interact with specifi c DNA sequences, and a C-terminal leucine zipper (bZIP) domain necessary for dimerization. Mutations in the CEBPA gene can occur across the entire gene, but occur most commonly in the N-terminal and C-terminal regions. N-terminal frameshift mutations truncate the wild-type protein and result in translation of a 30 kDa protein initiated at an internal ATG start site that lacks TAD1 and has a dominant negative eff ect. C-terminal mutations are generally in-frame insertions or deletions that result in disrupted DNA binding or dimerization [1 – 4]. Mutations in the CEBPA gene are detectable in 5 – 10% of cases of sporadic acute myeloid leukemia (AML). Th e majority of these patients have a double mutation, with mutations in both the N-terminus and C-terminus, while the remainder of the patients have only a single mutation. Th e favorable prognosis initially associated with CEBPA mutations in sporadic AML appears to be limited to patients with double mutations [1 – 4].

Conditioning Regimens for Cord Blood Transplantation

Conditioning regimens prior to allogeneic hematopoietic cell transplantation (allo-HCT) serve to suppress the patient’s immune system to allow infused progenitor and stem cells to engraft and, in the case of malignant diseases, to target residual disease to reduce relapse risk. Conditioning regimens vary in intensity; higher-intensity regimens result in increased risk of acute toxicity and potential regimen-related mortality, while lower-intensity regimens result in increased risk of relapse and graft failure. This chapter reviews myeloablative, reduced-intensity, and nonmyeloablative conditioning regimens used in cord blood transplantation to treat nonmalignant and neoplastic diseases. Special consideration is given to questions related to the role of antithymocyte globulin in conditioning regimens as well as strategies to optimize engraftment.

Alternative Sources of Hematopoietic Stem Cells and Their Clinical Applications

Reports on the therapeutic use of bone marrow for the treatment of anemia associated with leukemia or parasitic infections date back about one century (reviewed in [1]). However, it was not until the events at Alamagordo, New Mexico, and the observations in atomic bomb casualties at Hiroshima and Nagasaki that systematic research into hematopoietic stem cell transplantation (HSCT) got under way [2]. Studies on total body irradiation (TBI) in mice, rats, dogs, and nonhuman primates revealed three levels of TBI-related injury: a marrow (hematopoietic) syndrome at about 500–700 cGy, an intestinal syndrome at 1,200–10,000 cGy, and a cerebral syndrome at even higher doses [3]. In mice, shielding of the spleen during TBI, implantation of a syngeneic spleen, or infusion of syngeneic spleen or marrow cells after TBI rescued animals from the marrow syndrome [4, 5]. Intravenous injection was the most effective way of transplanting hematopoietic cells, which by way of “homing” reached the marrow cavity and other hematopoietic organs. These studies also showed that hematopoietic stem cells (HSC) were present at sites other than the marrow and were viable in the circulation. While the infusion of autologous or syngeneic cells rescued animals without complications, animals given cells from allogeneic donors developed “secondary disease,” now known as graft-vs.-host disease (GVHD) [3, 6].