In APL, the retinoic acid receptor alpha (RARα) gene on 17q12 fuses with a nuclear regulatory factor on 15q22 (promyelocytic leukemia or PML gene) resulting in a PML/RARα gene fusion transcript.[14,26,27] Rare cases of cryptic or masked t(15;17) lack typical cytogenetic findings and involve complex variant translocations or submicroscopic insertion of the RARα gene into PML gene leading to the expression of the PML/RARα fusion transcript. FISH and/or RT–PCR methods may be required to unmask these cryptic genetic rearrangements.[28,29]
APL has a specific sensitivity to treatment with all-trans retinoic acid (ATRA, tretinoin), which acts as a differentiating agent.[30,31,32] High complete remission rates in APL may be obtained by combining ATRA treatment with chemotherapy. In approximately 1% of the cases of APL, variant chromosomal aberrations may be found in which the RARα gene is fused with other genes. Variant translocations involving the RARα gene include: t(11;17)(q23; q21), t(5;17)(q32; q12) and t(11; 17)(q13; q21).
Acute myeloid leukemia with 11q23 (MLL) abnormalities
AML with 11q23 abnormalities comprises 5% to 6% of cases of AML and is typically associated with monocytic features. This AML is more common in children. Two clinical subgroups of patients have a high frequency of AML with 11q23 abnormalities: AML in infants and therapy-related AML, usually occurring after treatment with DNA topoisomerase inhibitors. Patients may present with DIC and extramedullary monocytic sarcomas and/or tissue infiltration (gingiva, skin).
Common morphologic features of this AML include the following:
- Monoblasts and promonocytes predominate in the bone marrow.
- Monoblasts and promonocytes with strong positive nonspecific esterase reactions.
11q23 abnormalities are associated frequently with acute myelomonocytic, monoblastic, and monocytic leukemias (FAB classifications M4, M5a and M5b, respectively) and occasionally with AML with and without maturation (FAB classifications M2 and M1, respectively).
The MLL gene on 11q23, a developmental regulator, is involved in translocations with approximately 22 different partner chromosomes.[13,14] Genes other than MLL may be involved in 11q23 abnormalities. FISH may be required to detect genetic abnormalities involving MLL.[35,36,37] In general, risk categories and prognoses for individual 11q23 translocations are difficult to determine because of the lack of studies involving significant numbers of patients; however, patients with t(11; 19)(q23; p13.1) are reported to have poor outcomes.
Acute Myeloid Leukemia With Mutations of FLT3, NPM1, or CMBPA
Activating mutations of FLT3 (FMS-like tyrosine kinase-3), present at diagnosis in 20% to 30% of de novo AML, represent the most frequent molecular abnormality in this disease.[38,39] The most common type of mutation (23%) is an internal tandem duplication mutation (FLT3/ITD) localized to the juxtamembrane region of the receptor, while point mutations in the kinase domain are less common (7%). Common clinical features of patients with FLT3/ITD AML are:
- Normal cytogenetics.
- Monocytic differentiation.