Transformation of pre B cells results in the development of pre-B cell-Acute Lymphoblastic Leukemia (B-ALL). In children, ALL (most of which are B-ALL) are the most common form of neoplasia. Thus, while treatment for pediatric B-ALL is highly effective (~80% survival), the 20% non-responders still represent a sizeable number of children that succumb to this disease. In addition, some types of ALL have a much poorer prognosis. Finally, while ALL is less common in adults, their outcome is much worse (~40% survival). A subset of B-ALL has been characterized by defects in genes involved in pre-BCR signaling, such as the adaptor protein Blnk. To explore the role of pre-BCR signaling in ALL, we crossed mice expressing a constitutively active STAT5b transgene (STAT5b-CA) to blnk+/-, btk-/-, pkc2-/-, or nf:b1-/- mice. STAT5b-CA mice develop ALL with very low penetrance (~1-2), while blnk+/-, btk-/-, pkc2-/-, and nf:b1-/- mice have not been reported to develop leukemia with increased frequency relative to WT mice. In contrast, 50-100% of STAT5b-CA x blnk+/-, STAT5b-CA x btk-/-,STAT5b-CA x pkc2-/-, and STAT5b-CA x nf:b1-/- mice developed B cell ALL within 300 days of birth. Based on these preliminary findings we hypothesize that signals leading to STAT5 activation, coupled with defects in pre-BCR signaling, cooperate to initiate ALL. Our results suggest a novel pairing of STAT5, and defective pre-BCR signaling, as cooperative oncogene and tumor suppressor pathway, respectively, that initiate ALL. In addition, our preliminary data indicate that STAT5 and NFkB signaling pathways play mutually antagonistic roles in non-transformed pre-B cells and that perturbation of this antagonistic feedback loop plays an important role in initiating pre-B ALL. We will test this hypothesis by (i) identifying the molecular mechanisms by which STAT5 entrains pre-B cell transformation, and (ii) determining how antagonism between STAT5 and NFkB signaling pathways prevents transformation. The significance of these proposed studies is underscored by our recent observations that (i) ~35% of human patients with ALL have increased levels of STAT5 activation, and (ii) patients with elevated levels of STAT5 activation prior to treatment have much poorer outcomes than those with lower levels of STAT5 activation. In summary, these studies should provide new insights into the molecular mechanisms by which activation of STAT5, coupled with defects pre-BCR signaling promotes the development of progenitor B-ALL;such information should result in more optimal therapies for B-ALL in the future.
Acute Lymphoblastic Leukemia (ALL) is the most common form of cancer in children. The studies supported by this grant will determine how deregulation of a molecule called STAT5 and a signaling pathway involving a cell surface receptor called the pre-BCR causes ALL. Our studies have implications for treatments directed at curing acute lymphoblastic leukemia and should lead to the development of new target molecules for pharmaceutical intervention in ALL.
|Manlove, Luke S; Schenkel, Jason M; Manlove, Kezia R et al. (2016) Heterologous Vaccination and Checkpoint Blockade Synergize To Induce Antileukemia Immunity. J Immunol 196:4793-804|
|Heltemes-Harris, L M; Larson, J D; Starr, T K et al. (2016) Sleeping Beauty transposon screen identifies signaling modules that cooperate with STAT5 activation to induce B-cell acute lymphoblastic leukemia. Oncogene 35:3454-64|
|Manlove, Luke S; Berquam-Vrieze, Katherine E; Pauken, Kristen E et al. (2015) Adaptive Immunity to Leukemia Is Inhibited by Cross-Reactive Induced Regulatory T Cells. J Immunol 195:4028-37|
|Liu, Grace J; Cimmino, Luisa; Jude, Julian G et al. (2014) Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia. Genes Dev 28:1337-50|
|Mahmud, Shawn A; Manlove, Luke S; Schmitz, Heather M et al. (2014) Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat Immunol 15:473-81|
|Mahmud, Shawn A; Manlove, Luke S; Farrar, Michael A (2013) Interleukin-2 and STAT5 in regulatory T cell development and function. JAKSTAT 2:e23154|
|Hodawadekar, Suchita; Park, Kyoungsook; Farrar, Michael A et al. (2012) A developmentally controlled competitive STAT5-PU.1 DNA binding mechanism regulates activity of the Ig Îº E3' enhancer. J Immunol 188:2276-84|
|Heltemes-Harris, Lynn M; Farrar, Michael A (2012) The role of STAT5 in lymphocyte development and transformation. Curr Opin Immunol 24:146-52|
|Johnson, Kristen; Chaumeil, Julie; Micsinai, Mariann et al. (2012) IL-7 functionally segregates the pro-B cell stage by regulating transcription of recombination mediators across cell cycle. J Immunol 188:6084-92|
|Heltemes-Harris, Lynn M; Willette, Mark J L; Ramsey, Laura B et al. (2011) Ebf1 or Pax5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia. J Exp Med 208:1135-49|