Does BCR/ABL1 positive Acute Myeloid Leukaemia Exist?

Abstract

Summary The BCR/ABL1 fusion gene, usually carried by the Philadelphia chromosome (Ph) resulting from t(9;22)(q34;q11) or variants, is pathognomonic for chronic myeloid leukaemia (CML). It is also occasionally found in acute lymphoblastic leukaemia (ALL) mostly in adults and rarely in de novo acute myeloid leukaemia (AML). Array Comparative Genomic Hybridization (aCGH) was used to study six Ph(+)AML, three bi‐lineage and four Ph(+)ALL searching for specific genomic profiles. Surprisingly, loss of the IKZF1 and/or CDKN2A genes, the hallmark of Ph(+)ALL, were recurrent findings in Ph(+)AML and accompanied cryptic deletions within the immunoglobulin and T cell receptor genes. The latter two losses have been shown to be part of ‘hot spot’ genome imbalances associated with BCR/ABL1 positive pre‐B lymphoid phenotype in CML and Ph(+)ALL. We applied Significance Analysis of Microarrays (SAM) to data from the ‘hot spot’ regions to the Ph(+)AML and a further 40 BCR/ABL1(+) samples looking for differentiating features. After exclusion of the most dominant markers, SAM identified aberrations unique to de novo Ph(+)AML that involved relevant genes. While the biological and clinical significance of this specific genome signature remains to be uncovered, the unique loss within the immunoglobulin genes provides a simple test to enable the differentiation of clinically similar de novo Ph(+) AML and myeloid blast crisis of CML.

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia

“…Preliminary data suggest that deletion of antigen receptor genes (IGH, TCR), IKZF1 and/or CDKN2A may support a diagnosis of de novo disease vs BP of CML. 80 Although the WHO authors struggled with how to incorporate the recent discoveries in gene mutations in AML, [81][82][83] the text for all disease categories is expanded to discuss the prognostic significance of various gene mutations and their frequency in the different AML subtypes. An updated table further summarizes the various genes mutated in AML and their significance (supplemental Table 2).…”

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

“…Distinction from blast phase of chronic myeloid leukemia may be difficult; preliminary data suggest that deletion of antigen receptor genes (immunoglobulin heavy chain and T-cell receptor), IKZF1, and/or CDKN2A may support a diagnosis of AML rather than chronic myeloid leukemia blast phase. 9 AML with mutated NPM1 and AML with biallelic mutations of CEBPA have become full entities; the latter category was restricted to cases with biallelic mutations because recent studies have shown that only those cases define the entity and portend a favorable outcome. [10][11][12][13][14][15][16] Both entities now subsume cases with multilineage dysplasia because presence of dysplasia lacks prognostic significance.…”

Acute Myeloid Leukemia with Both Meakaryoblastic & Basophilic Differentation

“…The second challenge arose when the Fish result showed positive Philadelphia chromosome, the question was whether it is Blast crisis of CML or Denovo AML with positive ph chromosome. Preliminary data suggest that additional molecular markers such as deletion of antigen receptor genes (IGH, TCR), IKZF1 and/or CDKN2A may support a diagnosis of de novo ABL over blast crisis of CML [7]. Unfortunately those molecular markers are not available in our laboratory.…”