Recurring chromosomal abnormalities in leukemia inPML-RARA transgenic mice parallel human acute promyelocytic leukemia

Abstract

Acute promyelocytic leukemia (APL) is characterized by the t(15;17)(q22;q11.2), which results in the PML-RARA fusion gene. In previous studies, we demonstrated that expression of a human PML-RARA complementary DNA in murine granulocyte precursor cells initiated the development of leukemia. However, leukemogenesis by PML-RARA required additional genetic alterations. To identify genetic changes that cooperate with PML-RARA in leukemogenesis, we performed spectral karyotyping analysis of myeloid leukemias from hMRP8-PML-RARA mice (11 cases) and from mice coexpressing PML-RARA and BCL2 (8 cases). Clonal abnormalities were detected in 18 of 19 cases (95%). Recurring numerical abnormalities identified in these murine leukemias included ؉15 (15 cases, 79%); loss of a sex chromosome (12 cases, 63%); ؉8 (10 cases, 53%); ؉10 (9 cases, 47%); ؉4, ؉7, or ؉14 (8 cases each, 42%); ؉16 (7 cases, 37%); and ؉6 (5 cases, 26%). In a series of 965 patients with APL, we identified secondary abnormalities in 368 (38%). The most common recurring abnormalities were ؉8 or partial trisomy of 8q (120 patients, 12.4%) and ider(17) t(15;17) (42 patients, 4.4%). The critical consequence of ؉8 in human leukemias appears to be the gain of 8q24, which is syntenic to mouse 15. Thus, our results suggest that PML-RARA-initiated murine leukemia is associated with a defined spectrum of genetic changes, and that these secondary mutations recapitulate, in part, the cytogenetic abnormalities found in human APL. (Blood. 2002;99:2985-2991

A microarray study of altered gene expression after cytarabine resistance in acute myeloid leukemia

“…Table 2 Ingenuity Systems genetic networks affected by Ara-C resistance The JAK2 1849G4T mutation results in valine to phenylalanine substitute at 617 amino acid (JAK2 V617F ), and this molecular change occurs in most patients with polycythemia vera (PV) and in approximately 50% of patients with essential thrombocythemia (ET) or chronic idiopathic myelofibrosis (CIMF). [1][2][3][4] Mitotic recombination at the terminal portion of the 9p region is considered to produce homozygous JAK2 V617F , and approximately 20-30% of PV patients have homozygous JAK2 V617F whereas most ET patients have heterozygous JAK2 V617F3 . However, it is still controversial whether JAK2 V617F is a primary genetic event in CMPD, and the frequency of homozygous JAK2 V617F varied in different reports, probably owing to technical differences or diagnostic criteria.…”

“…2,3 To characterize the sensitive and resistant lines, their chromosomal features were examined using spectral karyotyping analysis as described previously. 4 It is known that cell lines tend to manifest chromosomal abnormalities, especially after an extensive passaging process. As expected, both Ara-C-sensitive and -resistant cells show multiple chromosomal alterations, including chromosome loss, translocation and amplification (data not shown).…”

Acute promyelocytic leukemia: PML/RARα and the leukemic stem cell

“…37 Such an approach would permit one to study the exact contribution of each known genetic alteration to the induction of the leukemic phenotype without the background of chromosomal aberrations acquired during the development of late-onset leukemia in the PML/ RARa-transgenic mice. [38][39][40] PML/RARa and the differentiation of HSC Grignani et al 41 showed that PML/RARa enables human CD34 þ /linÀ cells to reach the promyelocytic level of differentiation but not to go further along the erythroid or the thrombocytic lineage, even if cells are cultivated in an adequate cytokine cocktail. These data strongly suggest a global differentiation block, which functions -at least for the erythroid and thrombocytic lineages -already at a very early level, whereas the granulocytic precursors are blocked at a later stage of differentiation: at the promyelocytic level.…”

Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1

“…We carried out cytogenetic and SKY analysis on spleen or bone marrow cells as described previously 11 .…”