Stem Cell and Leukemia Research

Researchers at Albert Einstein college of Medicine and Montefiore medical center have made important discoveries in the field of blood cancers. Some of the important ones are:

• Discovery of a new leukemia oncogene by Ulrich Steidl, MD, PhD. His lab discovered that the HLX gene (a homeobox transcription factor, H2.0-like homeobox) promotes acute myeloid leukemia. This new oncogene is overexpressed in the vast majority of patients with acute myeloid leukemia (AML) and independently correlates with inferior overall survival of AML patients. (Kawahara M, Pandolfi A, Bartholdy B, et al. H2.0-like homeobox regulates early hematopoiesis and promotes acute myeloid leukemia. Cancer Cell. 2012;22(2):194-208.)
• Identification of quantitative and qualitative stem cell alterations in MDS and demonstration of the role of "MDS stem cells" in disease relapse. This study from Amit Verma, MB, BS, and Dr. Steidl's labs was the first to show the alterations in MDS stem cells and demonstrated that these cells cannot be eradicated by standard treatments. (Will B, Zhou L, Vogler TO, et al. Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations. Blood. 2012;120(10):2076-86.)
• Discovery of IL1RAP as a novel marker of bad prognosis on the surface of these leukemia stem cells. Our studies have led to a clinical trial examining the role of AML stem cells in relapse and targeting of these stem cells with lenalidomide that will be conducted by Ira Braunschweig, MD. (Barreyro L, Will B, Bartholdy B, et al. Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. Blood. 2012;120(6):1290-98.)
• Discovery that a drug that increases platelets can also inhibit the growth of leukemia. Dr. Steidl's lab found that the. The novel small molecule thrombopoietin receptor agonist (eltrombopag) increases normal platelet formation without stimulating leukemia cell proliferation in vitro or in vivo (murine xenograft model), but rather inhibits the proliferation of leukemia cells by reducing intracellular iron and inducing differentiation. These findings provided the rationale for clinical evaluation of Eltrombopag for the treatment of thrombocytopenia in patients with AML and MDS and a trial of eltrombopag and lenalidomide initiated at Einstein by Dr. Verma. (Roth M, Will B, Simkin G, et al. Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation. Blood. 2012;120(20):386-94.)
• Development of a combination of immunotoxins and chemotherapy for treatment of acute lymphoblastic leukemia Combotox is a mixture of anti-CD19 and anti CD22 antibodies that are linked with a poison (ricin) that can target leukemic cells. Dr. Barta and Dr. Verma determined the optimum ways to combine these immunotoxins with chemotherapy and show that sequential combinations lead to syngeristic activity in vivo in mouse models. This work has led to a trial of combotox in combination with chemotherapy that is presently accruing patients at Einstein. This trial is led by Dr. Barta  (Schindler J, Gajavelli S, Ravandi F, et al. A phase I study of a combination of anti-CD19 and anti-CD22 immunotoxins (Combotox) in adult patients with refractory B-lineage acute lymphoblastic leukaemia. Br J Haematol. 2011;154(40):471-76; Barta SK, Zou Y, Schindler J, et al. Synergy of sequential administration of a deglycosylated ricin A chain-containing combined anti-CD19 and anti-CD22 immunotoxin (Combotox) and cytarabine in a murine model of advanced acute lymphoblastic leukemia. Leuk Lymphoma. 2012;53(10):1999-2003.)
• Identification of TGF-beta pathway inhibitors in the treatment of myelodysplastic syndromes. Work done in Dr. Verma's lab revesled that that inhibition of the TGF-β signaling pathway by genetic and pharmacologic means can stimulate blood formation in MDS. These findings strongly suggest that novel TGF-β receptor kinase inhibitors may be clinically useful in the treatment of MDS. (Zhou L, McMahon C, Bhagat T, et al. Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase. Cancer Res. 2011;71(3):955-63; Bhagat TD, Zhou L, Sokol L, et al. miR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling. Blood. 2013;121(15):2875-81.)