The FIP1L1-PDGFRA fusion gene is a recurrent molecular lesion in eosinophiliaassociated myeloproliferative disorders, predicting a favorable response to imatinib mesylate. To investigate its prevalence, 376 patients with persistent unexplained hypereosinophilia were screened by the United Kingdom reference laboratory, revealing 40 positive cases (11%).
The BCR-ABL1 fusion gene defines the subgroup of acute lymphoblastic leukemia (ALL) with the worst clinical prognosis. To identify oncogenic lesions that combine with BCR-ABL1 to cause ALL, we used Affymetrix Genome-Wide Human SNP arrays (250K NspI and SNP 6.0), fluorescence in situ hybridization, and genomic polymerase chain reaction to study 106 cases of adult BCR-ABL1-positive ALL. The most frequent somatic copy number alteration was a focal deletion on 7p12 of IKZF1, which encodes the transcription factor Ikaros and was identified in 80 (75%) of 106 patients. Different patterns of deletions occurred, but the most frequent were those characterized by a loss of exons 4 through 7 (⌬4-7) and by removal of exons 2 through 7 (⌬2-7). A variable number of nucleotides (patient specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. The extent of the ⌬4-7 deletion correlated with the expression of a dominant-negative isoform with cytoplasmic localization and oncogenic activity, whereas the ⌬2-7 deletion resulted in a transcript lacking the translation start site. The IKZF1 deletion also was identified in the progression of chronic myeloid leukemia to lymphoid blast crisis (66%) but never in myeloid blast crisis or chronicphase chronic myeloid leukemia or in patients with acute myeloid leukemia. Known DNA sequences and structural features were mapped along the breakpoint cluster regions, including heptamer recombination signal sequences recognized by RAG enzymes during V(D)J recombination, suggesting that IKZF1 deletions could arise from aberrant RAGmediated recombination. (Blood. 2009;
The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is known to play an important role in antiapoptotic signaling and has been implicated in the aggressiveness of a number of different human cancers including acute myelogenous leukemia (AML). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine, on human AML cells. Perifosine is a synthetic alkylphospholipid, a new class of antitumor agents, which target plasma membrane and inhibit signal transduction networks. Perifosine was tested on THP-1 and MV 4-11 cell lines, as well as primary leukemia cells. Perifosine treatment induced cell death by apoptosis in AML cell lines. Perifosine caused Akt and ERK 1/2 dephosphorylation as well as caspase activation. In THP-1 cells, the proapoptotic effect of perifosine was partly dependent on the Fas/FasL system and c-jun-N-kinase activation. In MV 4-11 cells, perifosine downregulated phosphorylated Akt, but not phosphorylated FLT3. Moreover, perifosine reduced the clonogenic activity of AML, but not normal, CD34 þ cells, and markedly increased blast cell sensitivity to etoposide. Our findings indicate that perifosine, either alone or in combination with existing drugs, might be a promising therapeutic agent for the treatment of those AML cases characterized by upregulation of the PI3K-Akt survival pathway.
The inv(16) cytogenetic subtype of acute myeloid leukemia (AML) has a relatively good prognosis. Many patients achieve complete remission (CR). The prognostic uncertainty of negative qualitative reverse transcription-polymerase chain reaction (RT-PCR) assays suggests the need to identify prognostically significant critical thresholds by real-time RT-PCR. A reliable and sensitive (10 ؊5 ) real-time RT-PCR assay was set up for the evaluation of relevant CBF-MYH11/ABL transcript ratios and was applied to the 21 patients with inv(16) AML routinely referred for cytogenetic and molecular monitoring in Serà gnoli Institute (Bologna, Italy) since 1990. Among the 18 patients who underwent ablative chemotherapy, all achieved CR with a 3-year disease-free survival probability of 63% (95% CI, 40%-87%) and no recorded events after 26 months. Five patients had relapses; 2 died of disease and 3 entered second CR. Analysis of the 125 bone marrow (or peripheral blood) samples studied by real-time RT-PCR showed that transcript ratios of samples taken during CR at any time before a relapse were always greater than 0.12%, whereas those of samples taken during first or second CR from patients who did not subsequently have relapses were always less than 0.25%. This suggests that transcript ratios greater than 0.25% may correspond to high risk for relapse, whereas ratios below 0.12% might indicate the patient is in a curable state.
IntroductionInversion of chromosome 16, inv(16)(p13q22), and its related translocation, t(16;16)(p13;q22), are recurrent rearrangements found in a subset of patients with acute myeloid leukemia (AML), particularly the M4Eo subtype. [1][2][3][4] Inv(16) is associated with relatively good long-term, disease-free survival (DFS). 5,6 It generates a chimeric mRNA transcript, CBF-MYH11, by fusing the CBF gene located on band q22 of chromosome 16 7,8 and the MYH11 gene, which encodes a heavy chain of the smooth-muscle myosin protein, located at the p13 breakpoint. 9,10 Messenger RNA analysis by reverse transcription-polymerase chain reaction (RT-PCR) can help define leukemic subsets and provide potentially valuable diagnostic and prognostic information. 11 Qualitative RT-PCR reveals the presence of detectable levels of minimal residual disease (MRD) in patients in complete clinical remission (CR) after induction chemotherapy. 12 Introduction of real-time RT-PCR 13 should allow routine quantitation of the transcript. The 5Ј-3Ј nuclease activity of the Taq polymerase cleaves an internal fluorogenic probe specific for the target sequence, causing the emission of a fluorescent signal that can be detected during amplification. This allows rapid quantitation of specific RT-PCR products with a dynamic detection range of more than 5 orders of magnitude. Several groups have used real-time RT-PCR with TaqMan technology to quantitate MRD with leukemia-specific chromosome aberrations such as t(9;22), t(l5;17), and t(8;21). [14][15][16] Most patients with inv(16) AML treated in our institute achieved long-term CR. 17,18 Ho...
Background
Deletions of IKAROS (
IKZF1
) frequently occur in B-cell precursor acute lymphoblastic leukemia (B-ALL) but the mechanisms by which they influence pathogenesis are unclear. To address this issue, a cohort of 144 adult B-ALL patients (106
BCR-ABL1
-positive and 38 B-ALL negative for known molecular rearrangements) was screened for
IKZF1
deletions by single nucleotide polymorphism (SNP) arrays; a sub-cohort of these patients (44%) was then analyzed for gene expression profiling.
Principal Findings
Total or partial deletions of
IKZF1
were more frequent in
BCR-ABL1
-positive than in
BCR-ABL1
-negative B-ALL cases (75%
vs
58%, respectively, p = 0.04). Comparison of the gene expression signatures of patients carrying
IKZF1
deletion
vs
those without showed a unique signature featured by down-regulation of B-cell lineage and DNA repair genes and up-regulation of genes involved in cell cycle,
JAK-STAT
signalling and stem cell self-renewal. Through chromatin immunoprecipitation and luciferase reporter assays we corroborated these findings both
in vivo
and
in vitro
, showing that Ikaros deleted isoforms lacked the ability to directly regulate a large group of the genes in the signature, such as
IGLL1
,
BLK
,
EBF1
,
MSH2, BUB3, ETV6, YES1, CDKN1A
(p21),
CDKN2C
(p18) and
MCL1
.
Conclusions
Here we identified and validated for the first time molecular pathways specifically controlled by
IKZF1
, shedding light into
IKZF1
role in B-ALL pathogenesis.
Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study defines incidence of chromothripsis in 395 newly diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix®) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had higher age (p = 0.002), ELN high risk (HR) (p < 0.001), lower white blood cell (WBC) count (p = 0.040), TP53 loss, and/or mutations (p < 0.001) while FLT3 (p = 0.025), and NPM1 (p = 0.032) mutations were mutually exclusive with chromothripsis. Chromothripsis-positive patients showed a worse overall survival (OS) (p < 0.001) compared with HR patients (p = 0.011) and a poor prognosis in a COX-HR optimal regression model. Chromothripsis presented the hallmarks of chromosome instability [i.e., TP53 alteration, 5q deletion, higher mean of copy number alteration (CNA), complex karyotype, alterations in DNA repair, and cell cycle] and focal deletions on chromosomes 4, 7, 12, 16, and 17. CBA. FISH showed that chromothripsis is associated with marker, derivative, and ring chromosomes. In conclusion, chromothripsis frequently occurs in AML (6.6%) and influences patient prognosis and disease biology.
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