Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia

Abstract

Arf tumor suppressor ͉ Gleevec ͉ IL-7 ͉ JAK kinases ͉ drug resistance

Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16Ink4a loss

“…Alternatively, the discrepancy may derive from differences in the cellular stress-response mechanisms elicited by cytotoxic agents versus targeted agents. In keeping with this latter explanation, the antileukemic response associated with targeted BCR-ABL inhibition is profoundly limited by p19 Arf deficiency in a mouse model (49). Likewise, p53 deficiency imparts resistance to targeted therapy in the context of BCR-ABLinduced leukemias (50), and our results imply that this resistance may stem from p19 Arf /p53 pathway compromise alone, without a need for additional perturbations in p16 Ink4a function.…”

The INK4-ARF (CDKN2A/B) Locus in Hematopoiesis and BCR-ABL-induced Leukemias

“…Introduction of these cells into healthy immunocompetent, syngeneic recipient host animals (hereafter "recipients") generates a fulminant ALL that quickly kills the mice. In direct contrast to the retarded leukemogenic potential of p185 + ;Arf +/+ cells in healthy animals, as few as 20 p185 + ;Arf -/-cells are capable of producing a disseminated pre-B-cell ALL in recipients in less than 4 weeks (Williams et al 2006(Williams et al , 2007. Abundant leukemic cells "marked" with green fluorescent protein (GFP) (expressed in tandem with BCR-ABL) can be recovered from all hematopoietic tissues of moribund animals and can be readily phenotyped, quantified, cultured in vitro, and efficiently transplanted serially and at the same limiting dilution into healthy secondary and tertiary recipients.…”

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

“…These include high hyperdiploidy, hypodiploidy, the translocations t(12;21)(p13;q22)[ETV6-RUNX1], t(1;19)(q23;p13.3) [TCF3-PBX1], t(9;22)(q34;q11)[BCR-ABL1] and rearrangement of the MLL gene at 11q23 in B-progenitor ALL, rearrangement of MYC in mature B-cell leukemia/lymphoma, and rearrangement of the TLX1 (HOX11), TLX3 (HOX11L2), LYL1, TAL1 and MLL genes in T-ALL. [8][9][10][11][12] These translocations frequently involve transcriptional regulators of hematopoiesis and are important initiating events in leukemogenesis, but the observations that these abnormalities are often detectable years before the onset of leukemia and usually do not alone result in leukemia in experimental models 13,14 suggest that cooperating genetic or epigenetic lesions are required. Candidate gene studies have identified lesions such as deletion of the CDKN2A/CDKN2B (encoding the tumor suppressors p16INK4A, p14ARF and p15INK4B) and NOTCH1 in T-ALL, [15][16][17][18] but until recently methods to analyze genetic alterations in a genome-wide fashion have been lacking.…”

“…This is supported by in vivo studies modeling the role of Pax5 haploinsufficiency in leukemogenesis. In a murine retroviral bone marrow transplant model of BCR-ABL1 B-progenitor ALL, 14,69 Pax5 haploinsufficiency increases the penetrance and reduces the latency of B-ALL . 70 Additional CNA of Pax5 and Cdkn2a/b, and sequence mutations of Pax5, were observed in the resulting murine tumors, further supporting a role for these alterations in leukemogenesis.…”