Investigators at Montefiore Einstein Center for Cancer Care (MECCC), Albert Einstein College of Medicine’s NCI–designated Albert Einstein Cancer Center and The Children’s Hospital at Montefiore will present their research findings at the American Society of Hematology’s (ASH) 57^th Annual Meeting and Exposition. Presentations include the first report on a genetic risk factor for avascular necrosis associated with treatment of acute lymphoblastic leukemia (ALL) in children along with new insights into the molecular basis for acute myeloid leukemia (AML) and a novel approach to the treatment of this disease. ASH 2015 will take place December 5-8, 2015 at the Orange County Convention Center in Orlando, Florida. 

Below are the Montefiore and Einstein oral presentations that will take place during the meeting. Researchers are available for media interviews.

 1.       Homozygosity for the 2R Tandem Repeat Polymorphism in the Thymidylate Synthase Promoter is Associated with Increased Risk for Bony Morbidity Among Children Treated for Acute Lymphoblastic Leukemia on DFCI Protocol—Presented by Peter D. Cole, M.D., associate professor of pediatrics, Einstein, and attending physician, Division of Hematology-Oncology, Department of Pediatrics, director, Hematologic Malignancy Service, Montefiore. Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Special Aspects of Childhood ALL.

Sunday, December 6, 1:00pm; Level 3, W331 (Orange County Convention Center).

• Bony morbidity—fractures or avascular necrosis (AVN) of bone—often complicates therapy for childhood ALL. This study of 626 children undergoing treatment on the Dana Farber Cancer Institute (DFCI) protocol for ALL tested 19 common genetic polymorphisms for possible association with bony morbidity. Homozygosity for the 2R thymidylate synthase polymorphism (2R/2R) was found in 129 20.6% of the patients tested and was associated with increased risk for bony morbidity. Interestingly, for children younger than 10, 2R/2R genotype was associated with a greater 5-year estimated incidence of AVN, while for children 10 and over, the increased risk was for fracture. This is the first report to identify a genetic risk for AVN specifically among children younger than 10, a group in which AVN occurs infrequently. This finding suggests that young children diagnosed with ALL and the 2R/2R genotype should be monitored closely for the development of AVN during ALL therapy.

 2.      Minimal Reduction of PU.1 is Sufficient to Induce a Preleukemic State and Promote Development of Acute Myeloid Leukemia—Presented by Britta Will, Ph.D,, assistant professor of medicine (oncology) and of cell biology, Einstein. Session: 602. Disordered Gene Expression in Hematologic Malignancy, including Disordered Epigenetic Regulation I.

Sunday, December 6; 4:30 PM, Level 3, W307 (Orange County Convention Center).

• Although near complete loss of the hematopoietic transcription factor PU.1 induces AML in mice, a similar degree of PU.1 impairment is exceedingly rare in human AML—yet moderate PU.1 inhibition is common in human AML, which mainly affects the elderly (median age greater than 65 at diagnosis). To test their hypothesis that even moderate gene-expression alterations in key regulators can drive malignant transformation, the researchers generated a novel mouse model with an accelerated accumulation of small sequence variations that resemble the mutation spectrum acquired in human hematopoietic stem cells during aging along with a heterozygous deletion of an upstream regulatory element of PU.1.
  Strikingly, reduction of PU.1 expression by only 26-37% in fractionated hematopoietic multipotent stem and myeloid progenitor cells triggered an aggressive, transplantable AML in more than two-thirds of mice. Overt leukemia was preceded by a preleukemic phase resembling human myelodysplastic syndrome (MDS). The study demonstrates that mutations in non-protein-coding regions of DNA—which often cause just modest alterations in protein levels—may actually play critical roles in causing MDS and AML and perhaps other diseases.

 3.     New Allosteric Inhibitors of Mutant IDH1 in Acute Myeloid Leukemia–Presented by Ujunwa

Cynthia Okoye-Okafor, M.D.-Ph.D. student in the lab of Ulrich Steidl, M.D., Ph.D., associate professor of cell biology and of medicine (oncology), Einstein, and associate chair for translational research, Department of Hematology/Oncology, Montefiore. Session: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Acute Myeloid Leukemia: Exploiting New Therapeutic Targets and Novel Technologies.

Monday, December 7, 4:30 PM, Level 3, W307 (Orange County Convention Center).

• Outcomes for patients with AML remain poor, especially for those over 60 who typically cannot tolerate high-dose chemotherapy and stem-cell transplantation. Since mutations of the isocitrate dehydrogenase 1 (IDH1) gene are known to drive AML, the researchers developed novel targeted allosteric inhibitors of mutant IDH1. for AML therapy. When the inhibitors were tested on AML patients’ cells that had differently clinically relevant IDH1 mutations, they uniformly decreased levels of the oncometabolite 2-hydroxyglutarate, abrogated the myeloid differentiation block, increased cell death and induced differentiation at the level of leukemic blasts and immature stem-like cells. The study reveals a promising new strategy using these and other allosteric inhibitors for targeting mutant IDH1 in leukemia and other cancers.   

 4.     Therapeutic Efficacy of Semisynthetic Supra Perfusion Resuscitation Fluids, EAF Peg Alb and EAF Peg Hb, Are Differentiated By Their Cerebral Effects in Animal Models of Sickle Cell Disease–Presented by Craig Branch, Ph.D., director of the Gruss Magnetic Resonance Research Center, Einstein. Session: 401. Basic Science and Clinical Practice in Blood Transfusion: Outcomes with Transfusion and Infusion Therapies Across Diverse Clinical Settings.

Monday, December 7, 5:30 PM. Level 3, W308 (Orange County Convention Center).

• Supra perfusion resuscitation fluids (SPF’s) enhance tissue perfusion, and can be used to supplement lost body fluid. The researchers used MRI to compare the therapeutic efficacy of two semisynthetic SPF’s, extension arm facilitated (EAF) PEG Alb and EAF PEG Hb,in wild type mice and in two anemic mouse models of Sickle Cell Disease (SCD), which they demonstrated to exhibit elevated cerebral blood flow. After infusing the two SFA’s, the wild type, non-SCD animals exhibited increased cerebral blood flow and improved tissue oxygen delivery. In contrast, after infusion of either SPF, the SCD animals exhibited increased blood flow in the systemic circulation but reduced cerebral blood flow in a disease-dependent fashion. The decreased perfusion associated with EAF PEG Alb increased cerebral hypoxia, while the effect on brain oxygenation was muted by the EAF PEG Hb, which provided additional oxygen to the brain. These divergent responses suggest the need to protect the cerebral circulation when developing SCD therapies aimed at reducing systemic venous occlusion associated with cell sickling.

 Montefiore and Einstein will also have three poster presentations focusing on improving outcomes for SCD.

In addition, Einstein medical student Nicholas Farris, who is mentored by Henny Billett, M.D., chief of the Division of Hematology, Department of Hematology/Oncology, Einstein and Montefiore, will receive an ASH Abstract Achievement Award for “Lack of Association of CNS Lesion Number with Cognitive Performance and Cerebral Blood Flow in Sickle Cell Disease.” Weijuan Li, Ph.D., will also receive the 2014 HONORS award for her research with Amit Verma, M.B.B.S., on MDS stem cells. Dr. Will and Dr. Okoye-Okafor will also receive abstract achievement awards for their research.