Multiple lines of evidence support a critical role of infections in the etiology of secondary lesions that initiate childhood leukemia. This led to the hypothesis that delayed exposure to common infections predisposes to childhood pre-B ALL. Early exposure to infectious pathogens, e.g. through daycare attendance or vaccinations, leads to mild and typically subclinical immune responses and is associated with a significantly diminished risk to develop childhood ALL. By contrast, delayed infections are often more serious, cause more vigorous immune responses and predispose to childhood pre-B ALL. The central goal of this proposal is to experimentally test the 'delayed infections'hypothesis and to delineate mechanisms of genetic vulnerability of human pre-B cells in the context of infection. Pre-B cells undergo Rag1/2-dependent immunoglobulin V(D)J gene recombination and represent the cell of origin of childhood ALL. Rag1/2-mediated recombinase activity causes DNA double strand breaks and is associated with a low risk to acquire chromosomal translocations. This risk, however, dramatically increases when Rag1/2 enzymes are expressed concomitantly with the B cell-specific mutator enzyme AID. Hence, expression of Rag1/2 and AID is mutually exclusive and temporally separated in early and late B cell development, respectively: Rag1 and Rag2 expression is limited to immunoglobulin V(D)J gene recombination in pro- and pre-B cells. Conversely, AID expression is thought to be restricted to somatic hypermutation and class-switch recombination in mature B cells that have encountered antigen. In preliminary work for this proposal, we found that IL7R?/Stat5/Akt signaling is critical to keep normal pre-B cells in an antigen- unresponsive state. Upon withdrawal of IL7 or conditional deletion of Stat5, pre-B cells become fully responsive to antigen (e.g. LPS) and express AID at similar levels as mature B cells upon LPS stimulation. While high levels of IL7 in the bone marrow secure pre-B cells in an antigen-unresponsive state, we discovered a window of vulnerability during normal pre-B cell differentiation: Pre-B cell receptor signaling downregulates IL7R? expression and induces Rag1/2-mediated immunoglobulin light chain gene recombination in small resting (Fraction D) pre-B cells. Upon antigen encounter, Fraction D pre-B cells express high levels of AID in addition to Rag1/2, which dramatically increases their propensity to chromosomal translocations. Based on these findings, we hypothesize that Fraction D pre-B cells are highly susceptible to genetic lesions in the context of infection. We propose the following three Aims to test the prediction that the size of the Fraction D pre-B cell pool and the frequency and intensity of immune responses to infections will determine the likelihood of a pre-leukemic (e.g. TEL-AML1) pre-B cell clone to acquire critical secondary lesions.
Acute lymphoblastic leukemia (ALL) represents the most frequent malignancy in children and teenagers and is common in adults as well. In 2008, 5,430 patients in the US were diagnosed with ALL (Leukemia and Lymphoma Society). Over the past four decades, the development of therapeutic options has greatly improved the prognosis of patients with ALL reaching 5 year disease-free survival rates of ~80% for children and ~55% for adults (Pui et al., 2004). Despite its relatively favorable overall prognosis, ALL remains one of the leading causes of person-years of life lost in the US (362,000 years in 2006;National Center of Health Statistics), which is attributed to the high incidence of ALL in children. Childhood ALL typically arises from a prenatally established pre-leukemic clone (Greaves and Wiemels, 2003). Genetic abnormalities that were acquired in utero are detected in cord blood samples, Guthrie cards and concordant twins who developed leukemia after a variable postnatal latency of up to 14 years. This led to a scenario, in which the initial prenatal lesion represents a first, albeit insufficient hit, which is followed by a series of additional transforming events, which ultimately cause leukemia (Greaves, 2009). Strikingly, some of these prenatal lesions define childhood leukemia subtypes yet are commonly detected in cord blood and on Guthrie cards from healthy individuals who will never develop disease. For instance, the TEL-AML1 gene rearrangement was detected in 6 of 567 (~1%) cord blood samples but leads to overt leukemia in less than 1% of these cases (with a cumulative risk of TEL- AML1 ALL at 1:14,000;Mori et al., 2004). These findings strongly support the notion that covert pre-leukemic clones are frequent but only a small minority of these pre-leukemic clones develop into frank leukemia after they acquired critical secondary genetic lesions. However, the postnatal mechanism(s) that drive the evolution of the fetal pre-leukemic clone towards childhood leukemia remain elusive and are at the center of this proposal. Since only a small minority of fetal pre-leukemic clones give rise to leukemia after birth, it appears critical to understand which mechanism(s) influence the clonal evolution of these pre-leukemic cells. This information will be highly significant, because control over these mechanisms could make childhood ALL a largely preventable disease.
|Xiao, Gang; Chan, Lai N; Klemm, Lars et al. (2018) B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies. Cell 173:470-484.e18|
|Martín-Lorenzo, Alberto; Auer, Franziska; Chan, Lai N et al. (2018) Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL. Cancer Res 78:2669-2679|
|Nieborowska-Skorska, Margaret; Sullivan, Katherine; Dasgupta, Yashodhara et al. (2017) Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. J Clin Invest 127:2392-2406|
|Graham, Nicholas A; Minasyan, Aspram; Lomova, Anastasia et al. (2017) Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. Mol Syst Biol 13:914|
|Gugliotta, Gabriele; Sudo, Makoto; Cao, Qi et al. (2017) Valosin-Containing Protein/p97 as a Novel Therapeutic Target in Acute Lymphoblastic Leukemia. Neoplasia 19:750-761|
|Chan, Lai N; Chen, Zhengshan; Braas, Daniel et al. (2017) Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 542:479-483|
|Xu, Liang; Chen, Ye; Dutra-Clarke, Marina et al. (2017) BCL6 promotes glioma and serves as a therapeutic target. Proc Natl Acad Sci U S A 114:3981-3986|
|Katerndahl, Casey D S; Heltemes-Harris, Lynn M; Willette, Mark J L et al. (2017) Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Nat Immunol 18:694-704|
|Schjerven, Hilde; Ayongaba, Etapong F; Aghajanirefah, Ali et al. (2017) Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre-B ALL. J Exp Med 214:793-814|
|McCracken, A N; McMonigle, R J; Tessier, J et al. (2017) Phosphorylation of a constrained azacyclic FTY720 analog enhances anti-leukemic activity without inducing S1P receptor activation. Leukemia 31:669-677|
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